🏷

Classifications

ISDS Skeletal Nosology

👪

Inheritance

1

Autosomal recessive inheritance HP:0000007

Seckel syndrome is genetically heterogeneous but classically follows autosomal recessive inheritance due to biallelic pathogenic variants in DNA damage response or centrosome-associated genes.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:36685824 SUPPORT Human Clinical

"Background: Seckel syndrome (SCKL) is a rare autosomal recessive inherited disorder, which is mainly characterized by intrauterine and postnatal growth restrictions, microcephaly, intellectual disability, and a typical "bird-head" facial appearance."

This recent family study directly supports autosomal recessive inheritance and the major clinical features of Seckel syndrome.

PMID:37371259 SUPPORT Human Clinical

"This novel variant, to the best of our knowledge, is pathogenic and with autosomal recessive inheritance expressed as Seckel syndrome in the affected members of the family."

This case report supports recessive inheritance in another molecularly solved Seckel-spectrum family.

◆

Subtypes

10

Seckel syndrome 1 (ATR) MONDO:0008869

ATR hgnc:882

The SCKL1 locus, mapped to chromosome 3q in two consanguineous Pakistani families and resolved to a synonymous ATR variant that alters splicing. It is the reference case for the DNA damage response arm of this entry: ATR is the checkpoint kinase whose function the affected fibroblasts lack.

Show evidence (1 reference)

PMID:12640452 SUPPORT Human Clinical

"We identified a synonymous mutation in affected individuals that alters ATR splicing."

The causal ATR variant in the two consanguineous families that define this subtype.

Seckel syndrome 2 (RBBP8/CtIP) MONDO:0011715

RBBP8 hgnc:9891

Caused by mutations in RBBP8, which encodes the DNA end-resection factor CtIP. The same gene also underlies Jawad syndrome, which the report describes as a similar form of congenital microcephaly; the two families carry different kinds of allele, an exonic frameshift in the Jawad family and a splicing variant yielding a dominant-negative CtIP in the SCKL2 family.

Show evidence (1 reference)

PMID:21998596 SUPPORT Human Clinical

"This work thus identifies CtIP as a disease gene for Seckel and Jawad syndromes and defines a new type of genetic disease mechanism in which a dominant negative mutation yields a recessively inherited disorder."

Establishes CtIP/RBBP8 as the SCKL2 gene and notes that the same gene gives Jawad syndrome.

Seckel syndrome 4 (CENPJ) MONDO:0013358

CENPJ hgnc:17272

The CENPJ form, whose mouse model is the source of this entry's centriole and mitotic failure node. HGNC has since renamed this gene CPAP, with CENPJ and MCPH6 as previous symbols; the label CENPJ is kept here because it is what the ontology build used for term validation returns for hgnc:17272.

Show evidence (1 reference)

PMID:37017437 SUPPORT Human Clinical

"Up to now, 40 patients with molecularly confirmed Seckel syndrome have been reported with biallelic variants in nine genes: ATR, CENPJ, CEP63, CEP152, DNA2, NIN, NSMCE2, RBBP8, and TRAIP."

Counts CENPJ among the nine genes in which biallelic variants give molecularly confirmed Seckel syndrome.

Seckel syndrome 5 (CEP152) MONDO:0013443

CEP152 hgnc:29298

The CEP152 form. The family curated here carried two novel variants found by trio exome sequencing, one of them a non-canonical splice-site change confirmed by RT-PCR to skip exon 12.

Show evidence (1 reference)

PMID:36685824 SUPPORT Human Clinical

"Two novel variants in CEP152, c.1060C>T (p.Arg354*) and c.1414-14A>G, were identified in the proband through trio-WES."

The two CEP152 variants identified in the family this subtype is named for.

Seckel syndrome 6 (CEP63) MONDO:0013871

CEP63 hgnc:25815

Biallelic loss-of-function variants in CEP63. Reported in two families; in the second, only one of three affected siblings had severe short stature, so the growth arm of the Seckel phenotype is variable in this subtype.

Show evidence (1 reference)

PMID:37017437 SUPPORT Human Clinical

"All siblings present with microcephaly, prominent nose, and intellectual disability but only one has severe short stature."

Records the within-family variability of short stature in the second reported CEP63 family.

Seckel syndrome 7 (NIN) MONDO:0013922

NIN hgnc:14906

The NIN form, reported in two sisters as a distinct microcephalic primordial dwarfism rather than under the Seckel label; MONDO carries "microcephalic primordial dwarfism, Dauber type" as a synonym of this term. Ninein is a centrosomal protein of asymmetric cell division, placing this subtype on the centrosomal rather than the DNA damage response arm.

Show evidence (1 reference)

PMID:22933543 SUPPORT Human Clinical

"NIN, encoding Ninein, a centrosomal protein critically involved in asymmetric cell division, was identified as a candidate gene, and functional impacts in fibroblasts and zebrafish were studied."

Identifies NIN and the centrosomal, asymmetric-division role that places this subtype on the centrosomal arm.

Seckel syndrome 8 (DNA2) MONDO:0014350

DNA2 hgnc:2939

Defined by a homozygous truncating DNA2 variant found in one consanguineous multiplex family during a genomic survey of primordial dwarfism. DNA2 is a replication-associated helicase/nuclease, so this subtype sits on the replication-stress arm.

Show evidence (1 reference)

PMID:24389050 SUPPORT Human Clinical

"In addition, we have identified a novel locus for Seckel syndrome based on a consanguineous multiplex family and identified a homozygous truncating mutation in DNA2 as the likely cause."

The family and the DNA2 variant that define this locus.

Seckel syndrome 9 (TRAIP) MONDO:0014767

TRAIP hgnc:30764

The TRAIP form. TRAIP is an E3 RING ubiquitin ligase acting at replication-blocking lesions, and the three reported patients had near-identical growth parameters with extreme disproportionate microcephaly.

Show evidence (1 reference)

PMID:26595769 SUPPORT Human Clinical

"Here we report the identification of mutations in TRAIP, encoding an E3 RING ubiquitin ligase, in patients with microcephalic primordial dwarfism."

Identifies TRAIP and the ubiquitin-ligase function that places this subtype on the replication-stress arm.

Seckel syndrome 10 (NSMCE2) MONDO:0014991

NSMCE2 hgnc:26513

The NSMCE2 form, and the weakest of the ten by expert-panel assessment: ClinGen classifies the relationship as Moderate on two reported patients. Those patients also had extreme insulin resistance and gonadal failure, features outside the Seckel core phenotype.

Show evidence (1 reference)

CGGV:assertion_ca7846fa-7685-4f47-b7e4-f4a9e3877664-2025-02-05T170000.000Z SUPPORT Other

"In summary, there is moderate evidence to support this gene-disease relationship."

ClinGen's own summary sentence for the NSMCE2 - Seckel syndrome 10 relationship, the basis for the caveat recorded here.

Seckel syndrome 11 (CEP295) MONDO:0958328

CEP295 hgnc:29366

The most recently described subtype, reported in four children from two unrelated families. The authors call the presentation Seckel-like rather than Seckel; MONDO files it as a direct subclass of Seckel syndrome. Loss of CEP295 reduces centriole and centrosome number and also produces primary ciliary defects in patient fibroblasts, which the report presents as a second arm of the pathogenesis alongside the centrosomal one.

Show evidence (1 reference)

PMID:38154379 SUPPORT In Vitro

"Mechanistically, depletion of CEP295 resulted in a decrease in the numbers of centrioles and centrosomes and triggered p53-dependent G1 cell cycle arrest."

The centriole/centrosome loss and p53-dependent arrest that make this a centrosomal-arm subtype. Graded IN_VITRO: the measurement was made in patient-derived fibroblasts and CEP295-depleted cell lines.

⚙

Pathophysiology

4

ATR-related DNA damage checkpoint disruption

A subset of Seckel syndrome genes affect ATR-dependent DNA damage response and replication-stress checkpoint signaling, linking genome-maintenance defects to impaired embryonic growth and neurodevelopment. RBBP8/CtIP is placed here rather than on the centrosomal arm because it generates the single-stranded DNA that ATR activation requires, so its loss disables the same checkpoint from one step upstream.

ATR hgnc:882 RBBP8 hgnc:9891

DNA damage response GO:0006974 ⚠ ABNORMAL DNA damage checkpoint signaling GO:0000077 ⚠ ABNORMAL

Downstream

Intrauterine growth retardation Genome-maintenance defects can impair embryonic growth.

Microcephaly Checkpoint and replication-stress defects can impair neurodevelopment.

Cataract Lens fibre cells are long-lived and replication-stress sensitive; reported in the RTTN case, and grouped here with no established route.

Ischemic stroke Reported in this disorder. Grouped here provisionally: a cerebrovascular arm is well established in the related PCNT disorder MOPD II, but no vasculopathy mechanism has been demonstrated for the Seckel genes.

Show evidence (4 references)

PMID:37371259 SUPPORT Human Clinical

"Forty cases of Seckel syndrome have been reported to date in the literature due to mutations in the ATR, TRAIP, RBBP8, NSMCE2, NIN, CENPJ, DNA2, CEP152 and CEP63 genes."

This supports ATR and other genome-maintenance genes as part of the heterogeneous Seckel syndrome gene set.

PMID:23166506 SUPPORT Model Organism

"Notably, however, genomic instability was not the result of defective ATR-dependent DNA damage signaling, as is the case for the majority of genes associated with Seckel syndrome."

This mouse-model abstract contrasts CENPJ disease with the usual ATR-dependent DNA damage signaling mechanism in many Seckel genes, so it partially supports this pathway as a recognized Seckel mechanism.

PMID:12640452 SUPPORT In Vitro

"A fibroblast cell line derived from an affected individual displays a defective DNA damage response caused by impaired ATR function."

A cultured patient-derived fibroblast line with a defective DNA damage response attributable to impaired ATR function. Graded IN_VITRO because the measurement was made in cultured cells, as for the parallel CtIP and CEP295 cell-line findings in this entry.

+ 1 more reference

Centrosome-dependent neural progenitor division impairment

Centrosome and centriole gene defects impair neural progenitor division, linking microtubule-organizing center dysfunction to reduced brain and body size.

neural progenitor cell CL:0011020

CEP152 hgnc:29298 CENPJ hgnc:17272 RTTN hgnc:18654 CEP63 hgnc:25815 NIN hgnc:14906 CEP295 hgnc:29366

centriole assembly GO:0098534 ⚠ ABNORMAL cell population proliferation GO:0008283 ↓ DECREASED

Downstream

Intrauterine growth retardation Impaired developmental cell proliferation contributes to prenatal growth restriction.

Microcephaly Impaired neural progenitor division contributes to reduced brain growth.

Short stature Global developmental proliferation defects contribute to severe postnatal growth restriction.

Intellectual disability Functional consequence of the reduced cortical neuron output that follows progenitor division failure.

Absent speech Grouped with the intellectual disability as a neurodevelopmental consequence; reported in the RTTN case and not a universal feature.

Narrow Face Craniofacial consequence of the generalized growth deficit; the bird-headed profile is the syndrome's defining gestalt but has no established mechanism.

Prominent Nose Part of the same craniofacial gestalt, with the same caveat.

Show evidence (5 references)

PMID:37443841 SUPPORT Human Clinical

"Most are caused by biallelic or, more rarely, dominant mutations in one of the likely hundreds of genes encoding PM proteins, i.e., ubiquitous centrosome or microtubule-associated proteins required for the division of neural progenitor cells in the embryonic brain."

This review links primary microcephaly and microcephalic dwarfism to centrosome or microtubule proteins needed for neural progenitor division.

PMID:37371259 SUPPORT Human Clinical

"The RTTN gene encodes centriole biogenesis, replication, symmetry and cohesion, basal body organization and has recently been associated with the appearance of microcephaly syndromes."

This supports RTTN as a centriole-associated gene relevant to microcephaly-spectrum Seckel disease.

PMID:22933543 SUPPORT Model Organism

"In the zebrafish, ninein knockdown led to specific and novel defects in the specification and morphogenesis of the anterior neuroectoderm, resulting in a deformity of the developing cranium with a small, squared skull highly reminiscent of the human phenotype."

Places NIN on this node: loss of ninein disrupts anterior neuroectoderm specification and cranial growth in vivo.

+ 2 more references

CENPJ-associated centriole and mitotic failure

CENPJ disruption impairs centriole and centrosome number control, causes abnormal mitotic spindles, DNA damage, apoptosis, and mitotic failure in a mouse model that recapitulates Seckel syndrome features.

embryonic fibroblast CL:0000057

CENPJ hgnc:17272

centriole replication GO:0007099 ⚠ ABNORMAL chromosome segregation GO:0007059 ⚠ ABNORMAL cell division GO:0051301 ⚠ ABNORMAL

Downstream

Intrauterine growth retardation Embryonic mitotic failure contributes to prenatal growth restriction.

Microcephaly CENPJ-associated developmental mitotic failure contributes to reduced brain growth.

Short stature Persistent growth impairment follows disrupted embryonic cell division.

Show evidence (3 references)

PMID:23166506 SUPPORT Model Organism

"By generating a hypomorphic allele of Cenpj, we have developed a mouse (Cenpj(tm/tm)) that recapitulates many of the clinical features of Seckel syndrome, including intrauterine dwarfism, microcephaly with memory impairment, ossification defects, and ocular and skeletal abnormalities, thus..."

This mouse model supports CENPJ disruption as a causal Seckel syndrome mechanism that reproduces key growth and neurologic phenotypes.

PMID:23166506 SUPPORT Model Organism

"Instead, Cenpj(tm/tm) embryonic fibroblasts exhibited irregular centriole and centrosome numbers and mono- and multipolar spindles, and many were near-tetraploid with numerical and structural chromosomal abnormalities when compared to passage-matched wild-type cells."

This directly supports abnormal centriole/centrosome control, spindle formation, and chromosomal instability as mechanistic consequences of Cenpj deficiency.

PMID:23166506 SUPPORT Model Organism

"Increased cell death due to mitotic failure during embryonic development is likely to contribute to the proportionate dwarfism that is associated with CENPJ-Seckel syndrome."

This supports mitotic failure and increased developmental cell death as a downstream route from CENPJ dysfunction to proportionate dwarfism.

Replication-stress intolerance in Seckel-spectrum genome maintenance genes

Three of the Seckel genes act on the replication fork itself rather than on the ATR checkpoint that reads it or on the centrosome that divides the cell. TRAIP is an E3 ubiquitin ligase recruited to damage during S phase, NSMCE2 is the SUMO ligase of the SMC5/6 complex, and DNA2 is a replication-associated nuclease-helicase. In each, patient or knockdown cells tolerate replicative stress poorly, and the resulting limit on developmental cell proliferation is the proposed route to the growth and brain-size phenotype. The node is kept separate from the ATR node because each of the three reports describes its gene acting at the fork itself rather than through ATR checkpoint signalling; that is a statement about what those reports show, not a claim that no such link exists.

TRAIP hgnc:30764 NSMCE2 hgnc:26513 DNA2 hgnc:2939

DNA repair GO:0006281 ⚠ ABNORMAL replication fork processing GO:0031297 ⚠ ABNORMAL

Downstream

Intrauterine growth retardation Limited proliferative capacity under replicative stress restricts embryonic growth.

Microcephaly The cited mechanism proposed for TRAIP: a limit on cellular proliferation reduces brain growth.

Short stature The same proliferative limit persists postnatally as severe growth restriction.

Show evidence (4 references)

PMID:26595769 SUPPORT In Vitro

"We establish that TRAIP relocalizes to sites of DNA damage, where it is required for optimal phosphorylation of H2AX and RPA2 during S-phase in response to ultraviolet (UV) irradiation, as well as fork progression through UV-induced DNA lesions."

Supports both bound processes for TRAIP: recruitment to DNA damage (DNA repair) and the requirement for replication fork progression past lesions (replication fork processing).

PMID:26595769 SUPPORT In Vitro

"TRAIP is necessary for efficient cell cycle progression and mutations in TRAIP therefore limit cellular proliferation, providing a potential mechanism for microcephaly and dwarfism phenotypes."

States the proposed route from this node to the growth and brain-size phenotypes, and is the basis for the downstream edges below.

PMID:25105364 SUPPORT In Vitro

"Collectively, these findings support a role for NSMCE2 in recovery from DNA damage and raise the possibility that loss of its function produces dwarfism through reduced tolerance of replicative stress."

Supports NSMCE2 on this node: a DNA damage recovery role whose loss the authors link to dwarfism through poor tolerance of replicative stress. Note the authors state this as a possibility rather than a demonstrated route.

+ 1 more reference

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

9

Cardiovascular 1

Ischemic stroke HP:0002140

Show evidence (1 reference)

DOI:10.1002/ccr3.8871 SUPPORT Human Clinical

"Seckel syndrome is a rare autosomal recessive disorder, characterized by growth retardation and multiple anomalies associated with CNS vasculopathy."

This case report abstract supports CNS vasculopathy as a complication; the article describes arterial stroke in the affected child.

Eye 1

Cataract HP:0000518

Show evidence (1 reference)

PMID:37371259 SUPPORT Human Clinical

"We present a consanguineous Pakistani family clinically suspected of Seckel syndrome with severe microcephaly, severe intellectual disability, short stature, absence of speech, pointed nose, narrow face and bilateral cataract in two siblings residing in the suburbs of Islamabad."

This case report directly supports bilateral cataract.

Head and Neck 3

Microcephaly HP:0000252

Show evidence (2 references)

PMID:36685824 SUPPORT Human Clinical

"Background: Seckel syndrome (SCKL) is a rare autosomal recessive inherited disorder, which is mainly characterized by intrauterine and postnatal growth restrictions, microcephaly, intellectual disability, and a typical "bird-head" facial appearance."

This directly lists microcephaly as a main Seckel syndrome feature.

PMID:37371259 SUPPORT Human Clinical

"We present a consanguineous Pakistani family clinically suspected of Seckel syndrome with severe microcephaly, severe intellectual disability, short stature, absence of speech, pointed nose, narrow face and bilateral cataract in two siblings residing in the suburbs of Islamabad."

This affected-family report supports severe microcephaly.

Prominent Nose HP:0000448

Show evidence (1 reference)

PMID:37371259 SUPPORT Human Clinical

"We present a consanguineous Pakistani family clinically suspected of Seckel syndrome with severe microcephaly, severe intellectual disability, short stature, absence of speech, pointed nose, narrow face and bilateral cataract in two siblings residing in the suburbs of Islamabad."

The case report directly supports a pointed/prominent nose.

Narrow Face HP:0000275

Show evidence (1 reference)

PMID:37371259 SUPPORT Human Clinical

"We present a consanguineous Pakistani family clinically suspected of Seckel syndrome with severe microcephaly, severe intellectual disability, short stature, absence of speech, pointed nose, narrow face and bilateral cataract in two siblings residing in the suburbs of Islamabad."

The case report directly supports narrow face.

Nervous System 2

Intellectual disability HP:0001249

Show evidence (1 reference)

PMID:36685824 SUPPORT Human Clinical

"Background: Seckel syndrome (SCKL) is a rare autosomal recessive inherited disorder, which is mainly characterized by intrauterine and postnatal growth restrictions, microcephaly, intellectual disability, and a typical "bird-head" facial appearance."

This directly lists intellectual disability as a main feature.

Absent speech HP:0001344

Show evidence (1 reference)

PMID:37371259 SUPPORT Human Clinical

"We present a consanguineous Pakistani family clinically suspected of Seckel syndrome with severe microcephaly, severe intellectual disability, short stature, absence of speech, pointed nose, narrow face and bilateral cataract in two siblings residing in the suburbs of Islamabad."

This family report directly supports absence of speech.

Growth 2

Intrauterine growth retardation HP:0001511

Show evidence (1 reference)

PMID:36685824 SUPPORT Human Clinical

"Background: Seckel syndrome (SCKL) is a rare autosomal recessive inherited disorder, which is mainly characterized by intrauterine and postnatal growth restrictions, microcephaly, intellectual disability, and a typical "bird-head" facial appearance."

The abstract identifies intrauterine growth restriction as a main disease characteristic.

Short stature HP:0004322

Show evidence (1 reference)

PMID:37371259 SUPPORT Human Clinical

"We present a consanguineous Pakistani family clinically suspected of Seckel syndrome with severe microcephaly, severe intellectual disability, short stature, absence of speech, pointed nose, narrow face and bilateral cataract in two siblings residing in the suburbs of Islamabad."

This case report directly includes short stature in affected siblings.

🧬

Genetic Associations

11

ATR (Causal biallelic variant)

Gene: ATR hgnc:882 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:37371259 SUPPORT Human Clinical

"Forty cases of Seckel syndrome have been reported to date in the literature due to mutations in the ATR, TRAIP, RBBP8, NSMCE2, NIN, CENPJ, DNA2, CEP152 and CEP63 genes."

This human case-report review identifies ATR among genes with mutations reported to cause Seckel syndrome.

CEP152 (Causal biallelic variant)

Gene: CEP152 hgnc:29298 gene page relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:36685824 SUPPORT Human Clinical

"Two novel variants in CEP152, c.1060C>T (p.Arg354*) and c.1414-14A>G, were identified in the proband through trio-WES."

This directly supports CEP152 as a causal Seckel syndrome gene.

PMID:36685824 SUPPORT Human Clinical

"Moreover, aberrant skipping of exon 12 due to the non-canonical splice-site variant was revealed by RT-PCR and Sanger sequencing."

This supports the functional effect of the non-canonical CEP152 splice variant.

RTTN (Causal biallelic variant)

Gene: RTTN hgnc:18654 relationship_type: UNKNOWN

Show evidence (2 references)

PMID:37371259 SUPPORT Human Clinical

"Whole-exome sequencing discovered NM_173630.4: c.57G > T(pGlu19Asp) missense variant in exon 2 of the RTTN gene that co-segregates in the family."

This supports RTTN as a Seckel-spectrum causal gene in the reported family.

CGGV:assertion_ebfb3367-c465-4e77-9256-ab34683c8ba7-2024-10-24T160000.000Z SUPPORT Other

ClinGen curates RTTN as Definitive, but against a different disease term from the Seckel one this entry models. Cited here so the UNKNOWN typing is read as being about the RTTN-to-Seckel pair and not about the gene.

CENPJ (Causal biallelic variant)

Gene: CENPJ hgnc:17272 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:23166506 SUPPORT Model Organism

"Disruption of the centromere protein J gene, CENPJ (CPAP, MCPH6, SCKL4), which is a highly conserved and ubiquitiously expressed centrosomal protein, has been associated with primary microcephaly and the microcephalic primordial dwarfism disorder Seckel syndrome."

This establishes CENPJ as a Seckel syndrome gene and supports the centriole-biogenesis mechanism.

RBBP8 (Causal biallelic variant)

Gene: RBBP8 hgnc:9891 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:21998596 SUPPORT Human Clinical

"This work thus identifies CtIP as a disease gene for Seckel and Jawad syndromes and defines a new type of genetic disease mechanism in which a dominant negative mutation yields a recessively inherited disorder."

Identifies CtIP (RBBP8) as a Seckel syndrome disease gene, which is the basis for this record.

PMID:21998596 SUPPORT Human Clinical

"Here, we report two mutations in the CtIP (RBBP8) gene within this locus that result in expression of C-terminally truncated forms of CtIP."

Names the two CtIP/RBBP8 mutations found at the SCKL2 locus and the truncated protein they produce.

CEP63 (Causal biallelic variant)

Gene: CEP63 hgnc:25815 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:37017437 SUPPORT Human Clinical

"Here, we report a second family with three siblings who are compound heterozygous for loss-of-function variants in CEP63, c.1125T>G, p.(Tyr375*) and c.595del, p.(Glu199Asnfs*11)."

A second family with biallelic loss-of-function CEP63 variants and a Seckel phenotype, which is the human evidence for this record.

NIN (Causal biallelic variant)

Gene: NIN hgnc:14906 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:22933543 SUPPORT Human Clinical

"From 34,606 genomic variants, two very rare missense variants in NIN were identified. Both probands were compound heterozygotes."

The exome finding in the two affected sisters that links NIN to this microcephalic primordial dwarfism phenotype.

PMID:37017437 SUPPORT Human Clinical

"Up to now, 40 patients with molecularly confirmed Seckel syndrome have been reported with biallelic variants in nine genes: ATR, CENPJ, CEP63, CEP152, DNA2, NIN, NSMCE2, RBBP8, and TRAIP."

Counts NIN among the genes in which biallelic variants give molecularly confirmed Seckel syndrome, which is why the NIN entity is curated here rather than only under its primordial-dwarfism name.

DNA2 (Causal biallelic variant)

Gene: DNA2 hgnc:2939 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:24389050 SUPPORT Human Clinical

"In addition, we have identified a novel locus for Seckel syndrome based on a consanguineous multiplex family and identified a homozygous truncating mutation in DNA2 as the likely cause."

The consanguineous-family mapping and homozygous truncating DNA2 variant that define the SCKL8 locus.

TRAIP (Causal biallelic variant)

Gene: TRAIP hgnc:30764 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:26595769 SUPPORT Human Clinical

"Here we report the identification of mutations in TRAIP, encoding an E3 RING ubiquitin ligase, in patients with microcephalic primordial dwarfism."

Identifies TRAIP mutations in microcephalic primordial dwarfism patients, the cohort from which the Seckel-diagnosed family in this report was drawn.

NSMCE2 (Causal biallelic variant)

Gene: NSMCE2 hgnc:26513 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:25105364 SUPPORT Human Clinical

"Here, we characterized 2 patients with primordial dwarfism, extreme insulin resistance, and gonadal failure and identified compound heterozygous frameshift mutations in NSMCE2."

The two patients and the compound heterozygous NSMCE2 frameshift variants that are the sole human case-level basis for this gene-disease pair.

CGGV:assertion_ca7846fa-7685-4f47-b7e4-f4a9e3877664-2025-02-05T170000.000Z SUPPORT Other

ClinGen's gene-disease validity row for NSMCE2 and Seckel syndrome 10, recording the Moderate classification and autosomal recessive inheritance.

CEP295 (Causal biallelic variant)

Gene: CEP295 hgnc:29366 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:38154379 SUPPORT Human Clinical

"Here, we report bi-allelic variants of CEP295 in four children from two unrelated families, characterized by severe primary microcephaly, short stature, developmental delay, intellectual disability, facial deformities, and abnormalities of fingers and toes, suggesting a Seckel-like syndrome."

The four affected children in two unrelated families and the phenotype the authors call Seckel-like, which is the human basis for this record.

💊

Medical Actions

1

Genetic counseling and reproductive planning

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Molecular diagnosis enables recurrence-risk counseling and reproductive planning in families affected by autosomal recessive Seckel syndrome.

Show evidence (1 reference)

PMID:36685824 SUPPORT Human Clinical

"Our findings expanded pathogenic variant spectra in SCKL and offered new insights into the pathogenicity of a non-classical splice-site variant in CEP152, which provided additional information for helping the family improve pregnancy plans in the future."

This supports genetic counseling and reproductive planning after a molecular diagnosis in an affected family.

🔬

Diagnosis

1

Molecular genetic testing

Molecular testing, including exome sequencing with confirmatory transcript studies when splice effects are suspected, can identify the causal gene and clarify recurrence risk in suspected Seckel syndrome.

molecular genetic testing NCIT:C19770

Results: Biallelic pathogenic variants in a Seckel syndrome gene support the diagnosis.

Show evidence (2 references)

PMID:36685824 SUPPORT Human Clinical

"We performed karyotype analysis, copy number variation sequencing (CNV-seq), and trio whole-exome sequencing (WES) to explore the genetic etiology in the proband."

This recent case demonstrates molecular diagnostic testing after clinical suspicion of Seckel syndrome.

PMID:36685824 SUPPORT Human Clinical

"The karyotype analysis and CNV-seq were normal in the proband. Two novel variants in CEP152, c.1060C>T (p.Arg354*) and c.1414-14A>G, were identified in the proband through trio-WES."

This supports exome sequencing as the diagnostic step that identified the causal variants after normal karyotype and CNV sequencing.

{ }

Source YAML

click to show

name: Seckel syndrome
creation_date: "2026-05-09T14:41:38Z"
description: >-
  Seckel syndrome is a rare autosomal recessive microcephalic primordial
  dwarfism syndrome characterized by prenatal and postnatal growth restriction,
  microcephaly, intellectual disability, and distinctive bird-headed
  craniofacial appearance.
category: Mendelian
parents:
- syndromic disease
- autosomal recessive disease
synonyms:
- SCKL
- Seckel-type dwarfism
- bird-headed dwarfism
disease_term:
  preferred_term: Seckel syndrome
  term:
    id: MONDO:0019342
    label: Seckel syndrome
classifications:
  isds_skeletal_category:
  - classification_value: primordial_dwarfism_and_slender_bones
    notes: >-
      ISDS Nosology of Genetic Skeletal Disorders, 2023 revision (Unger et al.,
      PMID:36779427), group 21 "Primordial dwarfism and slender bone
      dysplasias". Searching the 2023 table for "Seckel" returns nothing, which
      is a naming artefact rather than an omission: dyadic naming rewrote every
      Seckel row as "Microcephalic osteodysplastic primordial dwarfism,
      <GENE>-related", so the entities are identifiable only by gene and OMIM
      number. Six rows are Seckel syndrome - NOS 21-0110 (ATR, OMIM 210600 =
      Seckel syndrome 1), NOS 21-0120 (RBBP8, 606744 = SCKL2), NOS 21-0130
      (CEP152, 613823 = SCKL5), NOS 21-0140 (DNA2, 615807 = SCKL8), NOS 21-0150
      (TRAIP, 616777 = SCKL9) and NOS 21-0160 (NSMCE2, 617253 = SCKL10). This
      entry is the Seckel umbrella and so is broader than any single row; it is
      also broader than the group, because two of the genes curated here -
      CENPJ (SCKL4, OMIM 613676) and RTTN - appear nowhere in the 2023 table.
      Those two are not evidence of a second group: they are simply entities
      the committee did not list.
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    Seckel syndrome is genetically heterogeneous but classically follows
    autosomal recessive inheritance due to biallelic pathogenic variants in DNA
    damage response or centrosome-associated genes.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:36685824
    reference_title: Two novel variants in CEP152 caused Seckel syndrome 5 in a Chinese family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Background: Seckel syndrome (SCKL) is a rare autosomal recessive inherited disorder, which is mainly characterized by intrauterine and postnatal growth restrictions, microcephaly, intellectual disability, and a typical "bird-head" facial appearance.
    explanation: >-
      This recent family study directly supports autosomal recessive inheritance
      and the major clinical features of Seckel syndrome.
  - reference: PMID:37371259
    reference_title: "Microcephaly, Short Stature, Intellectual Disability, Speech Absence and Cataract Are Associated with Novel Bi-Allelic Missense Variant in RTTN Gene: A Seckel Syndrome Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This novel variant, to the best of our knowledge, is pathogenic and with autosomal recessive inheritance expressed as Seckel syndrome in the affected members of the family.
    explanation: >-
      This case report supports recessive inheritance in another molecularly
      solved Seckel-spectrum family.
pathophysiology:
- name: ATR-related DNA damage checkpoint disruption
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    A subset of Seckel syndrome genes affect ATR-dependent DNA damage response
    and replication-stress checkpoint signaling, linking genome-maintenance
    defects to impaired embryonic growth and neurodevelopment. RBBP8/CtIP is
    placed here rather than on the centrosomal arm because it generates the
    single-stranded DNA that ATR activation requires, so its loss disables the
    same checkpoint from one step upstream.
  genes:
  - preferred_term: ATR
    term:
      id: hgnc:882
      label: ATR
  - preferred_term: RBBP8
    term:
      id: hgnc:9891
      label: RBBP8
  biological_processes:
  - preferred_term: DNA damage response
    modifier: ABNORMAL
    term:
      id: GO:0006974
      label: DNA damage response
  - preferred_term: DNA damage checkpoint signaling
    modifier: ABNORMAL
    term:
      id: GO:0000077
      label: DNA damage checkpoint signaling
  evidence:
  - reference: PMID:37371259
    reference_title: "Microcephaly, Short Stature, Intellectual Disability, Speech Absence and Cataract Are Associated with Novel Bi-Allelic Missense Variant in RTTN Gene: A Seckel Syndrome Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Forty cases of Seckel syndrome have been reported to date in the literature due to mutations in the ATR, TRAIP, RBBP8, NSMCE2, NIN, CENPJ, DNA2, CEP152 and CEP63 genes.
    explanation: >-
      This supports ATR and other genome-maintenance genes as part of the
      heterogeneous Seckel syndrome gene set.
  - reference: PMID:23166506
    reference_title: "Disruption of mouse Cenpj, a regulator of centriole biogenesis, phenocopies Seckel syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Notably, however, genomic instability was not the result of defective ATR-dependent DNA damage signaling, as is the case for the majority of genes associated with Seckel syndrome.
    explanation: >-
      This mouse-model abstract contrasts CENPJ disease with the usual
      ATR-dependent DNA damage signaling mechanism in many Seckel genes, so it
      partially supports this pathway as a recognized Seckel mechanism.
  - reference: PMID:12640452
    reference_title: A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      A fibroblast cell line derived from an affected individual displays a defective DNA damage response caused by impaired ATR function.
    explanation: >-
      A cultured patient-derived fibroblast line with a defective DNA damage
      response attributable to impaired ATR function. Graded IN_VITRO because the
      measurement was made in cultured cells, as for the parallel CtIP and CEP295
      cell-line findings in this entry.
  - reference: PMID:21998596
    reference_title: CtIP Mutations Cause Seckel and Jawad Syndromes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Further characterization of cell lines derived from the SCKL2 family revealed defective DNA damage induced formation of single-stranded DNA, a critical co-factor for ATR activation.
    explanation: >-
      Places RBBP8/CtIP loss on this node: SCKL2 cells fail to generate the
      single-stranded DNA that ATR activation depends on.
  downstream:
  - target: Intrauterine growth retardation
    description: Genome-maintenance defects can impair embryonic growth.
  - target: Microcephaly
    description: Checkpoint and replication-stress defects can impair neurodevelopment.
  - target: Cataract
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Lens fibre cells are long-lived and replication-stress sensitive;
      reported in the RTTN case, and grouped here with no established route.
  - target: Ischemic stroke
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reported in this disorder. Grouped here provisionally: a cerebrovascular
      arm is well established in the related PCNT disorder MOPD II, but no
      vasculopathy mechanism has been demonstrated for the Seckel genes.
- name: Centrosome-dependent neural progenitor division impairment
  biological_scale: CELLULAR
  description: >-
    Centrosome and centriole gene defects impair neural progenitor division,
    linking microtubule-organizing center dysfunction to reduced brain and body
    size.
  genes:
  - preferred_term: CEP152
    term:
      id: hgnc:29298
      label: CEP152
  - preferred_term: CENPJ
    term:
      id: hgnc:17272
      label: CENPJ
  - preferred_term: RTTN
    term:
      id: hgnc:18654
      label: RTTN
  - preferred_term: CEP63
    term:
      id: hgnc:25815
      label: CEP63
  - preferred_term: NIN
    term:
      id: hgnc:14906
      label: NIN
  - preferred_term: CEP295
    term:
      id: hgnc:29366
      label: CEP295
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  biological_processes:
  - preferred_term: centriole assembly
    modifier: ABNORMAL
    term:
      id: GO:0098534
      label: centriole assembly
  - preferred_term: cell population proliferation
    modifier: DECREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  evidence:
  - reference: PMID:37443841
    reference_title: "Genetic Primary Microcephalies: When Centrosome Dysfunction Dictates Brain and Body Size."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most are caused by biallelic or, more rarely, dominant mutations in one of the likely hundreds of genes encoding PM proteins, i.e., ubiquitous centrosome or microtubule-associated proteins required for the division of neural progenitor cells in the embryonic brain.
    explanation: >-
      This review links primary microcephaly and microcephalic dwarfism to
      centrosome or microtubule proteins needed for neural progenitor division.
  - reference: PMID:37371259
    reference_title: "Microcephaly, Short Stature, Intellectual Disability, Speech Absence and Cataract Are Associated with Novel Bi-Allelic Missense Variant in RTTN Gene: A Seckel Syndrome Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The RTTN gene encodes centriole biogenesis, replication, symmetry and cohesion, basal body organization and has recently been associated with the appearance of microcephaly syndromes.
    explanation: >-
      This supports RTTN as a centriole-associated gene relevant to
      microcephaly-spectrum Seckel disease.
  - reference: PMID:22933543
    reference_title: Novel microcephalic primordial dwarfism disorder associated with variants in the centrosomal protein ninein.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In the zebrafish, ninein knockdown led to specific and novel defects in the specification and morphogenesis of the anterior neuroectoderm, resulting in a deformity of the developing cranium with a small, squared skull highly reminiscent of the human phenotype.
    explanation: >-
      Places NIN on this node: loss of ninein disrupts anterior neuroectoderm
      specification and cranial growth in vivo.
  - reference: PMID:38154379
    reference_title: "Bi-allelic variants in CEP295 cause Seckel-like syndrome presenting with primary microcephaly, developmental delay, intellectual disability, short stature, craniofacial and digital abnormalities."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mechanistically, depletion of CEP295 resulted in a decrease in the numbers of centrioles and centrosomes and triggered p53-dependent G1 cell cycle arrest.
    explanation: >-
      Places CEP295 on this node: its depletion lowers centriole and centrosome
      number and arrests proliferation.
  - reference: PMID:37017437
    reference_title: Expanding the phenotype of Seckel syndrome associated with biallelic loss-of-function variants in CEP63.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Up to now, 40 patients with molecularly confirmed Seckel syndrome have been reported with biallelic variants in nine genes: ATR, CENPJ, CEP63, CEP152, DNA2, NIN, NSMCE2, RBBP8, and TRAIP.
    explanation: >-
      Confirms CEP63 and NIN as Seckel genes. CEP63 is placed on this node on
      the strength of this confirmation plus its name - HGNC calls it
      "centrosomal protein 63" - rather than on a cited mechanism; no source in
      this entry describes what CEP63 does at the centrosome.
  downstream:
  - target: Intrauterine growth retardation
    description: Impaired developmental cell proliferation contributes to prenatal growth restriction.
  - target: Microcephaly
    description: Impaired neural progenitor division contributes to reduced brain growth.
  - target: Short stature
    description: Global developmental proliferation defects contribute to severe postnatal growth restriction.
  - target: Intellectual disability
    description: >-
      Functional consequence of the reduced cortical neuron output that
      follows progenitor division failure.
  - target: Absent speech
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Grouped with the intellectual disability as a neurodevelopmental
      consequence; reported in the RTTN case and not a universal feature.
  - target: Narrow Face
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Craniofacial consequence of the generalized growth deficit; the
      bird-headed profile is the syndrome's defining gestalt but has no established
      mechanism.
  - target: Prominent Nose
    description: >-
      Part of the same craniofacial gestalt, with the same caveat.
- name: CENPJ-associated centriole and mitotic failure
  biological_scale: CELLULAR
  description: >-
    CENPJ disruption impairs centriole and centrosome number control, causes
    abnormal mitotic spindles, DNA damage, apoptosis, and mitotic failure in a
    mouse model that recapitulates Seckel syndrome features.
  genes:
  - preferred_term: CENPJ
    term:
      id: hgnc:17272
      label: CENPJ
  cell_types:
  - preferred_term: embryonic fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: centriole replication
    modifier: ABNORMAL
    term:
      id: GO:0007099
      label: centriole replication
  - preferred_term: chromosome segregation
    modifier: ABNORMAL
    term:
      id: GO:0007059
      label: chromosome segregation
  - preferred_term: cell division
    modifier: ABNORMAL
    term:
      id: GO:0051301
      label: cell division
  evidence:
  - reference: PMID:23166506
    reference_title: "Disruption of mouse Cenpj, a regulator of centriole biogenesis, phenocopies Seckel syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      By generating a hypomorphic allele of Cenpj, we have developed a mouse (Cenpj(tm/tm)) that recapitulates many of the clinical features of Seckel syndrome, including intrauterine dwarfism, microcephaly with memory impairment, ossification defects, and ocular and skeletal abnormalities, thus providing clear confirmation that specific mutations of CENPJ can cause Seckel syndrome.
    explanation: >-
      This mouse model supports CENPJ disruption as a causal Seckel syndrome
      mechanism that reproduces key growth and neurologic phenotypes.
  - reference: PMID:23166506
    reference_title: "Disruption of mouse Cenpj, a regulator of centriole biogenesis, phenocopies Seckel syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Instead, Cenpj(tm/tm) embryonic fibroblasts exhibited irregular centriole and centrosome numbers and mono- and multipolar spindles, and many were near-tetraploid with numerical and structural chromosomal abnormalities when compared to passage-matched wild-type cells.
    explanation: >-
      This directly supports abnormal centriole/centrosome control, spindle
      formation, and chromosomal instability as mechanistic consequences of
      Cenpj deficiency.
  - reference: PMID:23166506
    reference_title: "Disruption of mouse Cenpj, a regulator of centriole biogenesis, phenocopies Seckel syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Increased cell death due to mitotic failure during embryonic development is likely to contribute to the proportionate dwarfism that is associated with CENPJ-Seckel syndrome.
    explanation: >-
      This supports mitotic failure and increased developmental cell death as a
      downstream route from CENPJ dysfunction to proportionate dwarfism.
  downstream:
  - target: Intrauterine growth retardation
    description: Embryonic mitotic failure contributes to prenatal growth restriction.
  - target: Microcephaly
    description: CENPJ-associated developmental mitotic failure contributes to reduced brain growth.
  - target: Short stature
    description: Persistent growth impairment follows disrupted embryonic cell division.
- name: Replication-stress intolerance in Seckel-spectrum genome maintenance genes
  biological_scale: MOLECULAR
  description: >-
    Three of the Seckel genes act on the replication fork itself rather than on
    the ATR checkpoint that reads it or on the centrosome that divides the cell.
    TRAIP is an E3 ubiquitin ligase recruited to damage during S phase, NSMCE2
    is the SUMO ligase of the SMC5/6 complex, and DNA2 is a
    replication-associated nuclease-helicase. In each, patient or knockdown
    cells tolerate replicative stress poorly, and the resulting limit on
    developmental cell proliferation is the proposed route to the growth and
    brain-size phenotype. The node is kept separate from the ATR node because
    each of the three reports describes its gene acting at the fork itself
    rather than through ATR checkpoint signalling; that is a statement about
    what those reports show, not a claim that no such link exists.
  genes:
  - preferred_term: TRAIP
    term:
      id: hgnc:30764
      label: TRAIP
  - preferred_term: NSMCE2
    term:
      id: hgnc:26513
      label: NSMCE2
  - preferred_term: DNA2
    term:
      id: hgnc:2939
      label: DNA2
  biological_processes:
  - preferred_term: DNA repair
    modifier: ABNORMAL
    term:
      id: GO:0006281
      label: DNA repair
  - preferred_term: replication fork processing
    modifier: ABNORMAL
    term:
      id: GO:0031297
      label: replication fork processing
  evidence:
  - reference: PMID:26595769
    reference_title: TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We establish that TRAIP relocalizes to sites of DNA damage, where it is required for optimal phosphorylation of H2AX and RPA2 during S-phase in response to ultraviolet (UV) irradiation, as well as fork progression through UV-induced DNA lesions.
    explanation: >-
      Supports both bound processes for TRAIP: recruitment to DNA damage (DNA
      repair) and the requirement for replication fork progression past lesions
      (replication fork processing).
  - reference: PMID:26595769
    reference_title: TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      TRAIP is necessary for efficient cell cycle progression and mutations in TRAIP therefore limit cellular proliferation, providing a potential mechanism for microcephaly and dwarfism phenotypes.
    explanation: >-
      States the proposed route from this node to the growth and brain-size
      phenotypes, and is the basis for the downstream edges below.
  - reference: PMID:25105364
    reference_title: Hypomorphism in human NSMCE2 linked to primordial dwarfism and insulin resistance.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Collectively, these findings support a role for NSMCE2 in recovery from DNA damage and raise the possibility that loss of its function produces dwarfism through reduced tolerance of replicative stress.
    explanation: >-
      Supports NSMCE2 on this node: a DNA damage recovery role whose loss the
      authors link to dwarfism through poor tolerance of replicative stress.
      Note the authors state this as a possibility rather than a demonstrated
      route.
  - reference: PMID:24389050
    reference_title: Genomic analysis of primordial dwarfism reveals novel disease genes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These results are highly suggestive that Seckel disease in this family is caused by marked DNA damage sensitivity due to DNA2 mutation.
    explanation: >-
      Supports DNA2 on this node: the authors attribute the family's Seckel
      disease to DNA damage sensitivity produced by the DNA2 variant, which they
      rescued by re-expressing wild-type DNA2 in patient cells.
  downstream:
  - target: Intrauterine growth retardation
    description: >-
      Limited proliferative capacity under replicative stress restricts
      embryonic growth.
  - target: Microcephaly
    description: >-
      The cited mechanism proposed for TRAIP: a limit on cellular proliferation
      reduces brain growth.
  - target: Short stature
    description: >-
      The same proliferative limit persists postnatally as severe growth
      restriction.
phenotypes:
- name: Intrauterine growth retardation
  category: Growth
  description: >-
    Prenatal growth restriction is a defining feature of Seckel syndrome and
    often persists as postnatal proportionate dwarfism.
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  evidence:
  - reference: PMID:36685824
    reference_title: Two novel variants in CEP152 caused Seckel syndrome 5 in a Chinese family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Background: Seckel syndrome (SCKL) is a rare autosomal recessive inherited disorder, which is mainly characterized by intrauterine and postnatal growth restrictions, microcephaly, intellectual disability, and a typical "bird-head" facial appearance.
    explanation: >-
      The abstract identifies intrauterine growth restriction as a main disease
      characteristic.
- name: Microcephaly
  category: Neurologic
  description: >-
    Microcephaly is a cardinal neurodevelopmental feature and can be severe.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:36685824
    reference_title: Two novel variants in CEP152 caused Seckel syndrome 5 in a Chinese family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Background: Seckel syndrome (SCKL) is a rare autosomal recessive inherited disorder, which is mainly characterized by intrauterine and postnatal growth restrictions, microcephaly, intellectual disability, and a typical "bird-head" facial appearance.
    explanation: This directly lists microcephaly as a main Seckel syndrome feature.
  - reference: PMID:37371259
    reference_title: "Microcephaly, Short Stature, Intellectual Disability, Speech Absence and Cataract Are Associated with Novel Bi-Allelic Missense Variant in RTTN Gene: A Seckel Syndrome Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present a consanguineous Pakistani family clinically suspected of Seckel syndrome with severe microcephaly, severe intellectual disability, short stature, absence of speech, pointed nose, narrow face and bilateral cataract in two siblings residing in the suburbs of Islamabad.
    explanation: This affected-family report supports severe microcephaly.
- name: Short stature
  category: Growth
  description: >-
    Severe postnatal growth restriction produces short stature within the
    microcephalic primordial dwarfism spectrum.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:37371259
    reference_title: "Microcephaly, Short Stature, Intellectual Disability, Speech Absence and Cataract Are Associated with Novel Bi-Allelic Missense Variant in RTTN Gene: A Seckel Syndrome Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present a consanguineous Pakistani family clinically suspected of Seckel syndrome with severe microcephaly, severe intellectual disability, short stature, absence of speech, pointed nose, narrow face and bilateral cataract in two siblings residing in the suburbs of Islamabad.
    explanation: This case report directly includes short stature in affected siblings.
- name: Intellectual disability
  category: Neurologic
  description: >-
    Intellectual disability is a major neurodevelopmental feature of the
    syndrome.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:36685824
    reference_title: Two novel variants in CEP152 caused Seckel syndrome 5 in a Chinese family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Background: Seckel syndrome (SCKL) is a rare autosomal recessive inherited disorder, which is mainly characterized by intrauterine and postnatal growth restrictions, microcephaly, intellectual disability, and a typical "bird-head" facial appearance.
    explanation: This directly lists intellectual disability as a main feature.
- name: Prominent Nose
  category: Craniofacial
  description: >-
    A pointed or prominent nose is a component of the characteristic
    bird-headed craniofacial appearance in reported Seckel-spectrum families.
  phenotype_term:
    preferred_term: Prominent nose
    term:
      id: HP:0000448
      label: Prominent nose
  evidence:
  - reference: PMID:37371259
    reference_title: "Microcephaly, Short Stature, Intellectual Disability, Speech Absence and Cataract Are Associated with Novel Bi-Allelic Missense Variant in RTTN Gene: A Seckel Syndrome Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present a consanguineous Pakistani family clinically suspected of Seckel syndrome with severe microcephaly, severe intellectual disability, short stature, absence of speech, pointed nose, narrow face and bilateral cataract in two siblings residing in the suburbs of Islamabad.
    explanation: The case report directly supports a pointed/prominent nose.
- name: Narrow Face
  category: Craniofacial
  description: >-
    A narrow face is a reported component of the Seckel-spectrum craniofacial
    gestalt.
  phenotype_term:
    preferred_term: Narrow face
    term:
      id: HP:0000275
      label: Narrow face
  evidence:
  - reference: PMID:37371259
    reference_title: "Microcephaly, Short Stature, Intellectual Disability, Speech Absence and Cataract Are Associated with Novel Bi-Allelic Missense Variant in RTTN Gene: A Seckel Syndrome Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present a consanguineous Pakistani family clinically suspected of Seckel syndrome with severe microcephaly, severe intellectual disability, short stature, absence of speech, pointed nose, narrow face and bilateral cataract in two siblings residing in the suburbs of Islamabad.
    explanation: The case report directly supports narrow face.
- name: Absent speech
  category: Neurologic
  description: >-
    Some affected individuals have severe speech and language impairment,
    including absence of speech.
  phenotype_term:
    preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  evidence:
  - reference: PMID:37371259
    reference_title: "Microcephaly, Short Stature, Intellectual Disability, Speech Absence and Cataract Are Associated with Novel Bi-Allelic Missense Variant in RTTN Gene: A Seckel Syndrome Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present a consanguineous Pakistani family clinically suspected of Seckel syndrome with severe microcephaly, severe intellectual disability, short stature, absence of speech, pointed nose, narrow face and bilateral cataract in two siblings residing in the suburbs of Islamabad.
    explanation: This family report directly supports absence of speech.
- name: Cataract
  category: Ophthalmologic
  description: >-
    Cataract is a reported ocular manifestation in some Seckel-spectrum
    families.
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:37371259
    reference_title: "Microcephaly, Short Stature, Intellectual Disability, Speech Absence and Cataract Are Associated with Novel Bi-Allelic Missense Variant in RTTN Gene: A Seckel Syndrome Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present a consanguineous Pakistani family clinically suspected of Seckel syndrome with severe microcephaly, severe intellectual disability, short stature, absence of speech, pointed nose, narrow face and bilateral cataract in two siblings residing in the suburbs of Islamabad.
    explanation: This case report directly supports bilateral cataract.
- name: Ischemic stroke
  category: Neurologic
  description: >-
    Cerebrovascular disease, including ischemic stroke related to CNS
    vasculopathy, has been reported as a serious complication in Seckel
    syndrome.
  phenotype_term:
    preferred_term: Ischemic stroke
    term:
      id: HP:0002140
      label: Ischemic stroke
  evidence:
  - reference: DOI:10.1002/ccr3.8871
    reference_title: Arterial stroke in a child with Seckel syndrome with a pattern of non-moyamoya vasculopathy
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seckel syndrome is a rare autosomal recessive disorder, characterized by growth retardation and multiple anomalies associated with CNS vasculopathy.
    explanation: >-
      This case report abstract supports CNS vasculopathy as a complication;
      the article describes arterial stroke in the affected child.
diagnosis:
- name: Molecular genetic testing
  description: >-
    Molecular testing, including exome sequencing with confirmatory transcript
    studies when splice effects are suspected, can identify the causal gene and
    clarify recurrence risk in suspected Seckel syndrome.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  results: >-
    Biallelic pathogenic variants in a Seckel syndrome gene support the
    diagnosis.
  evidence:
  - reference: PMID:36685824
    reference_title: Two novel variants in CEP152 caused Seckel syndrome 5 in a Chinese family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We performed karyotype analysis, copy number variation sequencing (CNV-seq), and trio whole-exome sequencing (WES) to explore the genetic etiology in the proband.
    explanation: >-
      This recent case demonstrates molecular diagnostic testing after clinical
      suspicion of Seckel syndrome.
  - reference: PMID:36685824
    reference_title: Two novel variants in CEP152 caused Seckel syndrome 5 in a Chinese family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The karyotype analysis and CNV-seq were normal in the proband. Two novel variants in CEP152, c.1060C>T (p.Arg354*) and c.1414-14A>G, were identified in the proband through trio-WES.
    explanation: >-
      This supports exome sequencing as the diagnostic step that identified the
      causal variants after normal karyotype and CNV sequencing.
has_subtypes:
- name: SCKL1
  display_name: Seckel syndrome 1 (ATR)
  subtype_term:
    preferred_term: Seckel syndrome 1
    term:
      id: MONDO:0008869
      label: Seckel syndrome 1
  genes:
  - preferred_term: ATR
    term:
      id: hgnc:882
      label: ATR
  description: >-
    The SCKL1 locus, mapped to chromosome 3q in two consanguineous Pakistani
    families and resolved to a synonymous ATR variant that alters splicing. It
    is the reference case for the DNA damage response arm of this entry: ATR is
    the checkpoint kinase whose function the affected fibroblasts lack.
  evidence:
  - reference: PMID:12640452
    reference_title: A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a synonymous mutation in affected individuals that alters ATR splicing.
    explanation: >-
      The causal ATR variant in the two consanguineous families that define this
      subtype.
- name: SCKL2
  display_name: Seckel syndrome 2 (RBBP8/CtIP)
  subtype_term:
    preferred_term: Seckel syndrome 2
    term:
      id: MONDO:0011715
      label: Seckel syndrome 2
  genes:
  - preferred_term: RBBP8
    term:
      id: hgnc:9891
      label: RBBP8
  description: >-
    Caused by mutations in RBBP8, which encodes the DNA end-resection factor
    CtIP. The same gene also underlies Jawad syndrome, which the report
    describes as a similar form of congenital microcephaly; the two families
    carry different kinds of allele, an exonic frameshift in the Jawad family
    and a splicing variant yielding a dominant-negative CtIP in the SCKL2
    family.
  evidence:
  - reference: PMID:21998596
    reference_title: CtIP Mutations Cause Seckel and Jawad Syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This work thus identifies CtIP as a disease gene for Seckel and Jawad syndromes and defines a new type of genetic disease mechanism in which a dominant negative mutation yields a recessively inherited disorder.
    explanation: >-
      Establishes CtIP/RBBP8 as the SCKL2 gene and notes that the same gene
      gives Jawad syndrome.
- name: SCKL4
  display_name: Seckel syndrome 4 (CENPJ)
  subtype_term:
    preferred_term: Seckel syndrome 4
    term:
      id: MONDO:0013358
      label: Seckel syndrome 4
  genes:
  - preferred_term: CENPJ
    term:
      id: hgnc:17272
      label: CENPJ
  description: >-
    The CENPJ form, whose mouse model is the source of this entry's centriole
    and mitotic failure node. HGNC has since renamed this gene CPAP, with CENPJ
    and MCPH6 as previous symbols; the label CENPJ is kept here because it is
    what the ontology build used for term validation returns for hgnc:17272.
  evidence:
  - reference: PMID:37017437
    reference_title: Expanding the phenotype of Seckel syndrome associated with biallelic loss-of-function variants in CEP63.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Up to now, 40 patients with molecularly confirmed Seckel syndrome have been reported with biallelic variants in nine genes: ATR, CENPJ, CEP63, CEP152, DNA2, NIN, NSMCE2, RBBP8, and TRAIP.
    explanation: >-
      Counts CENPJ among the nine genes in which biallelic variants give
      molecularly confirmed Seckel syndrome.
- name: SCKL5
  display_name: Seckel syndrome 5 (CEP152)
  subtype_term:
    preferred_term: Seckel syndrome 5
    term:
      id: MONDO:0013443
      label: Seckel syndrome 5
  genes:
  - preferred_term: CEP152
    term:
      id: hgnc:29298
      label: CEP152
  description: >-
    The CEP152 form. The family curated here carried two novel variants found
    by trio exome sequencing, one of them a non-canonical splice-site change
    confirmed by RT-PCR to skip exon 12.
  evidence:
  - reference: PMID:36685824
    reference_title: Two novel variants in CEP152 caused Seckel syndrome 5 in a Chinese family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two novel variants in CEP152, c.1060C>T (p.Arg354*) and c.1414-14A>G, were identified in the proband through trio-WES.
    explanation: >-
      The two CEP152 variants identified in the family this subtype is named
      for.
- name: SCKL6
  display_name: Seckel syndrome 6 (CEP63)
  subtype_term:
    preferred_term: Seckel syndrome 6
    term:
      id: MONDO:0013871
      label: Seckel syndrome 6
  genes:
  - preferred_term: CEP63
    term:
      id: hgnc:25815
      label: CEP63
  description: >-
    Biallelic loss-of-function variants in CEP63. Reported in two families; in
    the second, only one of three affected siblings had severe short stature,
    so the growth arm of the Seckel phenotype is variable in this subtype.
  evidence:
  - reference: PMID:37017437
    reference_title: Expanding the phenotype of Seckel syndrome associated with biallelic loss-of-function variants in CEP63.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All siblings present with microcephaly, prominent nose, and intellectual disability but only one has severe short stature.
    explanation: >-
      Records the within-family variability of short stature in the second
      reported CEP63 family.
- name: SCKL7
  display_name: Seckel syndrome 7 (NIN)
  subtype_term:
    preferred_term: Seckel syndrome 7
    term:
      id: MONDO:0013922
      label: Seckel syndrome 7
  genes:
  - preferred_term: NIN
    term:
      id: hgnc:14906
      label: NIN
  description: >-
    The NIN form, reported in two sisters as a distinct microcephalic primordial
    dwarfism rather than under the Seckel label; MONDO carries "microcephalic
    primordial dwarfism, Dauber type" as a synonym of this term. Ninein is a
    centrosomal protein of asymmetric cell division, placing this subtype on the
    centrosomal rather than the DNA damage response arm.
  evidence:
  - reference: PMID:22933543
    reference_title: Novel microcephalic primordial dwarfism disorder associated with variants in the centrosomal protein ninein.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NIN, encoding Ninein, a centrosomal protein critically involved in asymmetric cell division, was identified as a candidate gene, and functional impacts in fibroblasts and zebrafish were studied.
    explanation: >-
      Identifies NIN and the centrosomal, asymmetric-division role that places
      this subtype on the centrosomal arm.
- name: SCKL8
  display_name: Seckel syndrome 8 (DNA2)
  subtype_term:
    preferred_term: Seckel syndrome 8
    term:
      id: MONDO:0014350
      label: Seckel syndrome 8
  genes:
  - preferred_term: DNA2
    term:
      id: hgnc:2939
      label: DNA2
  description: >-
    Defined by a homozygous truncating DNA2 variant found in one consanguineous
    multiplex family during a genomic survey of primordial dwarfism. DNA2 is a
    replication-associated helicase/nuclease, so this subtype sits on the
    replication-stress arm.
  evidence:
  - reference: PMID:24389050
    reference_title: Genomic analysis of primordial dwarfism reveals novel disease genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, we have identified a novel locus for Seckel syndrome based on a consanguineous multiplex family and identified a homozygous truncating mutation in DNA2 as the likely cause.
    explanation: >-
      The family and the DNA2 variant that define this locus.
- name: SCKL9
  display_name: Seckel syndrome 9 (TRAIP)
  subtype_term:
    preferred_term: Seckel syndrome 9
    term:
      id: MONDO:0014767
      label: Seckel syndrome 9
  genes:
  - preferred_term: TRAIP
    term:
      id: hgnc:30764
      label: TRAIP
  description: >-
    The TRAIP form. TRAIP is an E3 RING ubiquitin ligase acting at
    replication-blocking lesions, and the three reported patients had
    near-identical growth parameters with extreme disproportionate microcephaly.
  evidence:
  - reference: PMID:26595769
    reference_title: TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report the identification of mutations in TRAIP, encoding an E3 RING ubiquitin ligase, in patients with microcephalic primordial dwarfism.
    explanation: >-
      Identifies TRAIP and the ubiquitin-ligase function that places this
      subtype on the replication-stress arm.
- name: SCKL10
  display_name: Seckel syndrome 10 (NSMCE2)
  subtype_term:
    preferred_term: Seckel syndrome 10
    term:
      id: MONDO:0014991
      label: Seckel syndrome 10
  genes:
  - preferred_term: NSMCE2
    term:
      id: hgnc:26513
      label: NSMCE2
  description: >-
    The NSMCE2 form, and the weakest of the ten by expert-panel assessment:
    ClinGen classifies the relationship as Moderate on two reported patients.
    Those patients also had extreme insulin resistance and gonadal failure,
    features outside the Seckel core phenotype.
  evidence:
  - reference: CGGV:assertion_ca7846fa-7685-4f47-b7e4-f4a9e3877664-2025-02-05T170000.000Z
    reference_title: NSMCE2 / Seckel syndrome 10 (Moderate)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In summary, there is moderate evidence to support this gene-disease relationship.
    explanation: >-
      ClinGen's own summary sentence for the NSMCE2 - Seckel syndrome 10
      relationship, the basis for the caveat recorded here.
- name: SCKL11
  display_name: Seckel syndrome 11 (CEP295)
  subtype_term:
    preferred_term: Seckel syndrome 11
    term:
      id: MONDO:0958328
      label: Seckel syndrome 11
  genes:
  - preferred_term: CEP295
    term:
      id: hgnc:29366
      label: CEP295
  description: >-
    The most recently described subtype, reported in four children from two
    unrelated families. The authors call the presentation Seckel-like rather
    than Seckel; MONDO files it as a direct subclass of Seckel syndrome. Loss of
    CEP295 reduces centriole and centrosome number and also produces primary
    ciliary defects in patient fibroblasts, which the report presents as a
    second arm of the pathogenesis alongside the centrosomal one.
  evidence:
  - reference: PMID:38154379
    reference_title: "Bi-allelic variants in CEP295 cause Seckel-like syndrome presenting with primary microcephaly, developmental delay, intellectual disability, short stature, craniofacial and digital abnormalities."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mechanistically, depletion of CEP295 resulted in a decrease in the numbers of centrioles and centrosomes and triggered p53-dependent G1 cell cycle arrest.
    explanation: >-
      The centriole/centrosome loss and p53-dependent arrest that make this a
      centrosomal-arm subtype. Graded IN_VITRO: the measurement was made in
      patient-derived fibroblasts and CEP295-depleted cell lines.
genetic:
- name: ATR
  association: Causal biallelic variant
  relationship_type: CAUSATIVE
  subtype: SCKL1
  gene_term:
    preferred_term: ATR
    term:
      id: hgnc:882
      label: ATR
  evidence:
  - reference: PMID:37371259
    reference_title: "Microcephaly, Short Stature, Intellectual Disability, Speech Absence and Cataract Are Associated with Novel Bi-Allelic Missense Variant in RTTN Gene: A Seckel Syndrome Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Forty cases of Seckel syndrome have been reported to date in the literature due to mutations in the ATR, TRAIP, RBBP8, NSMCE2, NIN, CENPJ, DNA2, CEP152 and CEP63 genes.
    explanation: >-
      This human case-report review identifies ATR among genes with mutations
      reported to cause Seckel syndrome.
- name: CEP152
  association: Causal biallelic variant
  relationship_type: CAUSATIVE
  subtype: SCKL5
  gene_term:
    preferred_term: CEP152
    term:
      id: hgnc:29298
      label: CEP152
  evidence:
  - reference: PMID:36685824
    reference_title: Two novel variants in CEP152 caused Seckel syndrome 5 in a Chinese family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two novel variants in CEP152, c.1060C>T (p.Arg354*) and c.1414-14A>G, were identified in the proband through trio-WES.
    explanation: This directly supports CEP152 as a causal Seckel syndrome gene.
  - reference: PMID:36685824
    reference_title: Two novel variants in CEP152 caused Seckel syndrome 5 in a Chinese family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Moreover, aberrant skipping of exon 12 due to the non-canonical splice-site variant was revealed by RT-PCR and Sanger sequencing.
    explanation: >-
      This supports the functional effect of the non-canonical CEP152 splice
      variant.
- name: RTTN
  association: Causal biallelic variant
  relationship_type: UNKNOWN
  notes: >-
    The cited family is described as clinically suspected Seckel syndrome, so
    RTTN is retained as a Seckel-spectrum association rather than a canonical
    founding SCKL gene. Typed UNKNOWN for the RTTN-to-Seckel pair specifically,
    not because the gene's pathogenicity is in doubt: ClinGen's Brain
    Malformations panel classifies RTTN as Definitive, but for microcephalic
    primordial dwarfism due to RTTN deficiency, a separate MONDO term. MONDO
    records no numbered Seckel subtype for RTTN, which is why this record carries
    no subtype key, and that other term is the better home for the gene.
  gene_term:
    preferred_term: RTTN
    term:
      id: hgnc:18654
      label: RTTN
  evidence:
  - reference: PMID:37371259
    reference_title: "Microcephaly, Short Stature, Intellectual Disability, Speech Absence and Cataract Are Associated with Novel Bi-Allelic Missense Variant in RTTN Gene: A Seckel Syndrome Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing discovered NM_173630.4: c.57G > T(pGlu19Asp) missense variant in exon 2 of the RTTN gene that co-segregates in the family.
    explanation: >-
      This supports RTTN as a Seckel-spectrum causal gene in the reported
      family.
  - reference: CGGV:assertion_ebfb3367-c465-4e77-9256-ab34683c8ba7-2024-10-24T160000.000Z
    reference_title: "RTTN / microcephalic primordial dwarfism due to RTTN deficiency (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      RTTN | HGNC:18654 | microcephalic primordial dwarfism due to RTTN deficiency | MONDO:0018764 | AR | Definitive | SOP11 | Brain Malformations Gene Curation Expert Panel | 2024-10-24T16:00:00.000Z
    explanation: >-
      ClinGen curates RTTN as Definitive, but against a different disease term
      from the Seckel one this entry models. Cited here so the UNKNOWN typing is
      read as being about the RTTN-to-Seckel pair and not about the gene.
- name: CENPJ
  association: Causal biallelic variant
  relationship_type: CAUSATIVE
  subtype: SCKL4
  gene_term:
    preferred_term: CENPJ
    term:
      id: hgnc:17272
      label: CENPJ
  evidence:
  - reference: PMID:23166506
    reference_title: "Disruption of mouse Cenpj, a regulator of centriole biogenesis, phenocopies Seckel syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Disruption of the centromere protein J gene, CENPJ (CPAP, MCPH6, SCKL4), which is a highly conserved and ubiquitiously expressed centrosomal protein, has been associated with primary microcephaly and the microcephalic primordial dwarfism disorder Seckel syndrome.
    explanation: >-
      This establishes CENPJ as a Seckel syndrome gene and supports the
      centriole-biogenesis mechanism.
- name: RBBP8
  association: Causal biallelic variant
  relationship_type: CAUSATIVE
  subtype: SCKL2
  gene_term:
    preferred_term: RBBP8
    term:
      id: hgnc:9891
      label: RBBP8
  notes: >-
    RBBP8 encodes CtIP, the DNA end-resection factor that generates the
    single-stranded DNA on which ATR is activated, so this gene sits upstream of
    the ATR checkpoint arm rather than on the centrosomal arm. HGNC lists SCKL2
    as a previous symbol for RBBP8.
  evidence:
  - reference: PMID:21998596
    reference_title: CtIP Mutations Cause Seckel and Jawad Syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This work thus identifies CtIP as a disease gene for Seckel and Jawad syndromes and defines a new type of genetic disease mechanism in which a dominant negative mutation yields a recessively inherited disorder.
    explanation: >-
      Identifies CtIP (RBBP8) as a Seckel syndrome disease gene, which is the
      basis for this record.
  - reference: PMID:21998596
    reference_title: CtIP Mutations Cause Seckel and Jawad Syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report two mutations in the CtIP (RBBP8) gene within this locus that result in expression of C-terminally truncated forms of CtIP.
    explanation: >-
      Names the two CtIP/RBBP8 mutations found at the SCKL2 locus and the
      truncated protein they produce.
- name: CEP63
  association: Causal biallelic variant
  relationship_type: CAUSATIVE
  subtype: SCKL6
  gene_term:
    preferred_term: CEP63
    term:
      id: hgnc:25815
      label: CEP63
  evidence:
  - reference: PMID:37017437
    reference_title: Expanding the phenotype of Seckel syndrome associated with biallelic loss-of-function variants in CEP63.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report a second family with three siblings who are compound heterozygous for loss-of-function variants in CEP63, c.1125T>G, p.(Tyr375*) and c.595del, p.(Glu199Asnfs*11).
    explanation: >-
      A second family with biallelic loss-of-function CEP63 variants and a
      Seckel phenotype, which is the human evidence for this record.
- name: NIN
  association: Causal biallelic variant
  relationship_type: CAUSATIVE
  subtype: SCKL7
  gene_term:
    preferred_term: NIN
    term:
      id: hgnc:14906
      label: NIN
  notes: >-
    The report that identified NIN describes the two sisters as a novel subtype
    of microcephalic primordial dwarfism rather than using the Seckel label;
    MONDO carries "microcephalic primordial dwarfism, Dauber type" as a synonym
    of Seckel syndrome 7, and a later Seckel review counts NIN among the nine
    genes with molecularly confirmed Seckel syndrome.
  evidence:
  - reference: PMID:22933543
    reference_title: Novel microcephalic primordial dwarfism disorder associated with variants in the centrosomal protein ninein.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      From 34,606 genomic variants, two very rare missense variants in NIN were identified. Both probands were compound heterozygotes.
    explanation: >-
      The exome finding in the two affected sisters that links NIN to this
      microcephalic primordial dwarfism phenotype.
  - reference: PMID:37017437
    reference_title: Expanding the phenotype of Seckel syndrome associated with biallelic loss-of-function variants in CEP63.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Up to now, 40 patients with molecularly confirmed Seckel syndrome have been reported with biallelic variants in nine genes: ATR, CENPJ, CEP63, CEP152, DNA2, NIN, NSMCE2, RBBP8, and TRAIP.
    explanation: >-
      Counts NIN among the genes in which biallelic variants give molecularly
      confirmed Seckel syndrome, which is why the NIN entity is curated here
      rather than only under its primordial-dwarfism name.
- name: DNA2
  association: Causal biallelic variant
  relationship_type: CAUSATIVE
  subtype: SCKL8
  gene_term:
    preferred_term: DNA2
    term:
      id: hgnc:2939
      label: DNA2
  evidence:
  - reference: PMID:24389050
    reference_title: Genomic analysis of primordial dwarfism reveals novel disease genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, we have identified a novel locus for Seckel syndrome based on a consanguineous multiplex family and identified a homozygous truncating mutation in DNA2 as the likely cause.
    explanation: >-
      The consanguineous-family mapping and homozygous truncating DNA2 variant
      that define the SCKL8 locus.
- name: TRAIP
  association: Causal biallelic variant
  relationship_type: CAUSATIVE
  subtype: SCKL9
  gene_term:
    preferred_term: TRAIP
    term:
      id: hgnc:30764
      label: TRAIP
  evidence:
  - reference: PMID:26595769
    reference_title: TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report the identification of mutations in TRAIP, encoding an E3 RING ubiquitin ligase, in patients with microcephalic primordial dwarfism.
    explanation: >-
      Identifies TRAIP mutations in microcephalic primordial dwarfism patients,
      the cohort from which the Seckel-diagnosed family in this report was drawn.
- name: NSMCE2
  association: Causal biallelic variant
  relationship_type: CAUSATIVE
  subtype: SCKL10
  gene_term:
    preferred_term: NSMCE2
    term:
      id: hgnc:26513
      label: NSMCE2
  notes: >-
    ClinGen's Syndromic Disorders expert panel classifies the NSMCE2 - Seckel
    syndrome 10 relationship as Moderate rather than Definitive, so the record
    is retained but the strength of the assertion is weaker than for ATR or
    CENPJ. The two reported patients also had extreme insulin resistance and
    gonadal failure, which are not features of the Seckel core phenotype.
  evidence:
  - reference: PMID:25105364
    reference_title: Hypomorphism in human NSMCE2 linked to primordial dwarfism and insulin resistance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we characterized 2 patients with primordial dwarfism, extreme insulin resistance, and gonadal failure and identified compound heterozygous frameshift mutations in NSMCE2.
    explanation: >-
      The two patients and the compound heterozygous NSMCE2 frameshift variants
      that are the sole human case-level basis for this gene-disease pair.
  - reference: CGGV:assertion_ca7846fa-7685-4f47-b7e4-f4a9e3877664-2025-02-05T170000.000Z
    reference_title: NSMCE2 / Seckel syndrome 10 (Moderate)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      NSMCE2 | HGNC:26513 | Seckel syndrome 10 | MONDO:0014991 | AR | Moderate | SOP11 | Syndromic Disorders Gene Curation Expert Panel | 2025-02-05T17:00:00.000Z
    explanation: >-
      ClinGen's gene-disease validity row for NSMCE2 and Seckel syndrome 10,
      recording the Moderate classification and autosomal recessive inheritance.
- name: CEP295
  association: Causal biallelic variant
  relationship_type: CAUSATIVE
  subtype: SCKL11
  gene_term:
    preferred_term: CEP295
    term:
      id: hgnc:29366
      label: CEP295
  notes: >-
    The report describes the four affected children as having a Seckel-like
    syndrome rather than using the Seckel diagnosis itself; MONDO nonetheless
    files the CEP295 entity as Seckel syndrome 11, a direct subclass of Seckel
    syndrome. HGNC lists KIAA1731 as a previous symbol for CEP295.
  evidence:
  - reference: PMID:38154379
    reference_title: "Bi-allelic variants in CEP295 cause Seckel-like syndrome presenting with primary microcephaly, developmental delay, intellectual disability, short stature, craniofacial and digital abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report bi-allelic variants of CEP295 in four children from two unrelated families, characterized by severe primary microcephaly, short stature, developmental delay, intellectual disability, facial deformities, and abnormalities of fingers and toes, suggesting a Seckel-like syndrome.
    explanation: >-
      The four affected children in two unrelated families and the phenotype
      the authors call Seckel-like, which is the human basis for this record.
treatments:
- name: Genetic counseling and reproductive planning
  description: >-
    Molecular diagnosis enables recurrence-risk counseling and reproductive
    planning in families affected by autosomal recessive Seckel syndrome.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:36685824
    reference_title: Two novel variants in CEP152 caused Seckel syndrome 5 in a Chinese family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings expanded pathogenic variant spectra in SCKL and offered new insights into the pathogenicity of a non-classical splice-site variant in CEP152, which provided additional information for helping the family improve pregnancy plans in the future.
    explanation: >-
      This supports genetic counseling and reproductive planning after a
      molecular diagnosis in an affected family.
clinical_trials: []
datasets: []
biochemical: []
environmental: []

📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 46 citations 2026-05-09T10:55:45.184681

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Seckel syndrome
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Seckel syndrome covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Seckel syndrome (microcephalic primordial dwarfism): disease characteristics report

Target disease

Disease name: Seckel syndrome
Category: Mendelian (autosomal recessive microcephalic primordial dwarfism)
Core concept: A genetically heterogeneous syndrome in which impaired genome maintenance (DNA damage response/replication stress) and/or centrosome–centriole dysfunction leads to profound prenatal-onset growth failure with severe microcephaly and neurodevelopmental impairment. (farcy2023geneticprimarymicrocephalies pages 2-4, zhang2023twonovelvariants pages 1-2, mcintyre2012disruptionofmouse pages 1-2)

1. Disease information

1.1 Definition and overview (current understanding)

Seckel syndrome is classically defined by symmetrical intrauterine growth restriction (IUGR) and postnatal proportionate short stature, severe microcephaly, intellectual disability, and characteristic craniofacial features often described as “bird-headed” (prominent nose/beaked nose and micrognathia). (zhang2023twonovelvariants pages 1-2, farcy2023geneticprimarymicrocephalies pages 2-4, kelana2023caseofseckel pages 1-2)

A recent review of centrosome-related microcephalies places Seckel syndrome within microcephalic primordial dwarfism (MPD) and summarizes diagnostic “threshold-like” anthropometrics, including childhood short stature around −6 to −8 SD and adult height around ~120 cm, with markedly reduced head circumference (adult ~39–42 cm, newborn ~27 cm in the cited clinical criteria). (farcy2023geneticprimarymicrocephalies pages 2-4)

Source types: The overview above is derived from aggregated disease-level resources and reviews plus patient-level case reports (e.g., variant discovery and stroke case report). (zhang2023twonovelvariants pages 1-2, mudassir2023microcephalyshortstature pages 1-2, alavi2024arterialstrokein pages 3-4)

1.2 Key identifiers (as available in retrieved evidence)

OMIM: Seckel syndrome (OMIM #210600) (farcy2023geneticprimarymicrocephalies pages 2-4)
Orphanet: ORPHA:808 (jentcy2021seckelsyndrome pages 1-1)
MeSH-like identifiers in ClinicalTrials.gov records: “Seckel syndrome 1” (C537533) appears in an observational study record. (NCT03139903 chunk 1)

Not found in the retrieved sources (therefore not asserted here): MONDO ID, ICD-10/ICD-11 code(s), and canonical MeSH descriptor ID for Seckel syndrome.

1.3 Common synonyms / alternative names

“Seckel syndrome” is frequently discussed as a Seckel syndrome spectrum within MPD and in historical nosology (e.g., “Primary autosomal recessive microcephalies and Seckel syndrome spectrum disorders”). (jurca2024clinicalchallengesin pages 1-2, zhang2023twonovelvariants pages 8-8)
“Microcephalic primordial dwarfism” is often used as the broader clinical grouping. (jentcy2021seckelsyndrome pages 1-1, jurca2024clinicalchallengesin pages 1-2)

2. Etiology

2.1 Primary causal factors

Genetic (germline) biallelic pathogenic variants are the primary causal factor, consistent with autosomal recessive inheritance. (kelana2023caseofseckel pages 1-2, jurca2024clinicalchallengesin pages 4-6)

Seckel syndrome is genetically heterogeneous. For example, a 2023 gene-discovery-oriented case report states: “Forty cases of Seckel syndrome have been reported to date in the literature due to mutations in the ATR, TRAIP, RBBP8, NSMCE2, NIN, CENPJ, DNA2, CEP152 and CEP63 genes,” while also presenting RTTN as an additional cause in their family. (mudassir2023microcephalyshortstature pages 1-2)

2.2 Risk factors

Major risk factor: Having biallelic (recessive) pathogenic variants in one of multiple causal genes (see Section 4). (mudassir2023microcephalyshortstature pages 1-2, zhang2023twonovelvariants pages 1-2)
Family history/consanguinity: Many gene-discovery case reports are from consanguineous families (e.g., RTTN and CEP152 reports), supporting a recessive architecture but without population-level quantification in the retrieved excerpts. (mudassir2023microcephalyshortstature pages 1-2, zhang2023twonovelvariants pages 1-2)

2.3 Protective factors / gene–environment interactions

No protective factors or specific gene–environment interactions were identified in the retrieved evidence. Given the congenital Mendelian etiology, environmental modifiers are plausible but not established here.

3. Phenotypes

3.1 Core phenotypes (with ontology suggestions)

Below are high-frequency, defining features. Frequency data are limited in the retrieved sources; where quantitative estimates exist, they are provided.

1) Prenatal-onset growth restriction / primordial dwarfism - Typical onset: prenatal (IUGR) with persistent postnatal growth restriction. (farcy2023geneticprimarymicrocephalies pages 2-4, kelana2023caseofseckel pages 1-2) - HPO suggestions: HP:0001511 (Intrauterine growth restriction), HP:0004322 (Short stature), HP:0000252 (Microcephaly).

2) Severe microcephaly with neurodevelopmental impairment - Phenotype type: clinical sign (microcephaly), symptom domain (intellectual disability). (farcy2023geneticprimarymicrocephalies pages 2-4, zhang2023twonovelvariants pages 1-2) - HPO suggestions: HP:0000252 (Microcephaly), HP:0001249 (Intellectual disability).

3) Craniofacial dysmorphology (“bird-headed” facies) - Reported features: prominent/beaked nose, narrow face, micrognathia, prominent eyes. (kelana2023caseofseckel pages 1-2, alavi2024arterialstrokein pages 2-3) - HPO suggestions: HP:0000365 (Low-set ears), HP:0000347 (Micrognathia), HP:0000411 (Prominent nose) [or equivalent HPO term], HP:0000520 (Proptosis) (as applicable).

4) Congenital anomalies / multisystem involvement (variable) - Reviews and case series note possible cardiovascular anomalies and myelodysplasia among additional features in some patients. (zhang2023twonovelvariants pages 1-2) - HPO suggestions: HP:0001627 (Abnormality of the cardiovascular system), HP:0001875 (Neutropenia)/HP:0001890 (Thrombocytopenia) if myelodysplasia manifests.

3.2 Notable complications with quantitative data: CNS vasculopathy / stroke

A 2024 case report (with literature synthesis) reports that CNS vasculopathy occurs in 3.16% (8/253) of Seckel syndrome patients and that moyamoya disease accounts for 1.97%; reported mean age 13.5 years (range 6–19) with equal sex distribution. (alavi2024arterialstrokein pages 4-4)

Clinical presentations can include headache, seizures, weakness/coma, and imaging findings such as carotid narrowing/obliteration, collateral formation, aneurysms, infarcts, and hemorrhage. (alavi2024arterialstrokein pages 4-4)

HPO suggestions: HP:0001297 (Stroke), HP:0001344 (Cerebral aneurysm), HP:0001324 (Hemiplegia), HP:0002073 (Cerebral infarction).

3.3 Quality of life / function (reported intervention outcomes)

A single-case rehabilitation report using proprioceptive neuromuscular facilitation (PNF/Kabat) in an 18-year-old describes objective functional changes: Short Physical Performance Battery (SPPB) improved from 4 to 8, Timed Up and Go (TUG) improved from 28.0 s to 19.9 s, and grip strength increased 23.4% (right) and 27.4% (left), while ADL scale and DASH did not show significant improvements. (souza2022seckelsyndromecase pages 8-11, souza2022seckelsyndromecase pages 11-12)

4. Genetic / molecular information

4.1 Causal genes (examples supported in retrieved evidence)

Evidence supports biallelic pathogenic variants across multiple modules:

DNA damage response / replication stress genes (ATR pathway and partners): - ATR, RBBP8 (CtIP), DNA2, TRAIP, NSMCE2 (listed across review/case sources as Seckel/MPD-associated). (mudassir2023microcephalyshortstature pages 1-2, mcintyre2012disruptionofmouse pages 1-2, patrick2017atrisa pages 58-61)

Centrosome/centriole and mitotic spindle genes: - CENPJ, CEP152, CEP63, NIN, CDK5RAP2, RTTN. (mcintyre2012disruptionofmouse pages 1-2, zhang2023twonovelvariants pages 1-2, mudassir2023microcephalyshortstature pages 1-2)

A 2023 study notes that Seckel syndrome 5 (SCKL5; MIM#613823) is caused by pathogenic variants in CEP152, which encodes a centrosomal protein involved in centrosome duplication and genome integrity / DNA damage responses. (zhang2023twonovelvariants pages 1-2)

4.2 Pathogenic variants (explicit examples from 2023–2024 literature in this corpus)

CEP152: c.1060C>T (p.Arg354*, nonsense) and c.1414-14A>G (non-canonical splice variant) were identified by trio-WES; RT-PCR showed exon 12 skipping for the splice variant. (zhang2023twonovelvariants pages 1-2)
RTTN: NM_173630.4:c.57G>T (p.Glu19Asp, missense) reported in a consanguineous Pakistani family with Seckel syndrome features and cataract; discovered by WES. (mudassir2023microcephalyshortstature pages 1-2)

Variant interpretation framework: The CEP152 paper explicitly used confirmatory molecular approaches (qPCR/RT-PCR/Sanger) consistent with clinical variant interpretation practices. (zhang2023twonovelvariants pages 1-2)

4.3 Functional consequences (high-level)

Across the gene set above, a convergent theme is impaired: - DNA replication-stress response and checkpoint signaling (ATR pathway), and/or - centrosome/centriole integrity and spindle assembly leading to genomic instability, mitotic failure, and cell loss during development. (patrick2017atrisa pages 58-61, mcintyre2012disruptionofmouse pages 1-2)

Population allele frequencies: Not extractable from the retrieved evidence excerpts; therefore not asserted.

5. Environmental information

No specific environmental, lifestyle, or infectious contributors were identified in the retrieved evidence; Seckel syndrome is presented as a congenital Mendelian disorder. (kelana2023caseofseckel pages 1-2, mudassir2023microcephalyshortstature pages 1-2)

6. Mechanism / pathophysiology

6.1 Mechanistic model (causal chain)

A practical synthesis supported by primary and review literature:

1) Upstream trigger: biallelic loss-of-function or hypomorphic variants in genes controlling DNA damage response/replication stress (e.g., ATR module) and/or centrosome–centriole biogenesis/spindle function (e.g., CENPJ/CEP152/RTTN module). (patrick2017atrisa pages 58-61, mcintyre2012disruptionofmouse pages 1-2, mudassir2023microcephalyshortstature pages 1-2) 2) Cellular consequence: defective checkpoint/repair and/or abnormal centriole number/structure → abnormal mitoses, aneuploidy/micronuclei, replication-associated DNA damage, and increased apoptosis. (mcintyre2012disruptionofmouse pages 1-2, mcintyre2012disruptionofmouse pages 6-8) 3) Tissue/developmental consequence: impaired proliferation/survival of neural progenitors and other growth-critical lineages during embryogenesis → severe microcephaly and proportionate primordial dwarfism. (farcy2023geneticprimarymicrocephalies pages 2-4, mcintyre2012disruptionofmouse pages 1-2)

A key mechanistic statement from the Cenpj mouse model study is that “increased cell death due to mitotic failure during embryonic development is likely to contribute to the proportionate dwarfism.” (mcintyre2012disruptionofmouse pages 1-2)

6.2 Pathways, processes, cell types (ontology suggestions)

GO Biological Process (examples): - DNA replication checkpoint / response to replication stress (GO terms associated with ATR module) - DNA damage response, signal transduction by p53 class mediator (for downstream apoptosis) - Centrosome duplication / centriole assembly - Mitotic spindle organization

CL Cell types (examples, mechanistically relevant): - Neural progenitor cell (radial glia) (primary microcephaly mechanism context) (farcy2023geneticprimarymicrocephalies pages 2-4)

Note: Specific GO and CL identifiers are not explicitly enumerated in the retrieved text excerpts; the above are mechanistically aligned suggestions based on the described biology.

6.3 Visual evidence (genes/pathways summary)

Cropped figures/tables from a 2023 review summarize Seckel/MPD genes and their functional localization at the centrosome/spindle and DNA repair pathways. (farcy2023geneticprimarymicrocephalies media eb9668c0, farcy2023geneticprimarymicrocephalies media 1a99a141, farcy2023geneticprimarymicrocephalies media 0b042e40, farcy2023geneticprimarymicrocephalies media c608a08c)

7. Anatomical structures affected

7.1 Organ/system level (high-level)

Central nervous system: microcephaly and neurodevelopmental impairment are core; cerebrovascular involvement (moyamoya/non-moyamoya vasculopathy, aneurysms, infarcts/hemorrhage) is a clinically important complication in a minority. (farcy2023geneticprimarymicrocephalies pages 2-4, alavi2024arterialstrokein pages 4-4, alavi2024arterialstrokein pages 3-4)
Craniofacial skeleton: characteristic craniofacial dysmorphology is typical. (kelana2023caseofseckel pages 1-2)

7.2 Tissue/cell level

Developmentally critical proliferative compartments (especially neural progenitors) are implicated by the primary microcephaly/MPD framework and the cited centrosome/DDR mechanisms. (farcy2023geneticprimarymicrocephalies pages 2-4, mcintyre2012disruptionofmouse pages 1-2)

7.3 Subcellular level (GO Cellular Component suggestions)

Centrosome/centriole and mitotic spindle compartments are repeatedly implicated across causal genes (e.g., CEP152, CENPJ, RTTN). (zhang2023twonovelvariants pages 1-2, mcintyre2012disruptionofmouse pages 1-2, mudassir2023microcephalyshortstature pages 1-2)

8. Temporal development

Onset: typically congenital/prenatal (IUGR, congenital microcephaly). (farcy2023geneticprimarymicrocephalies pages 2-4, kelana2023caseofseckel pages 1-2)
Course: lifelong short stature and microcephaly; neurodevelopmental impairments are persistent. Rare but serious later complications include cerebrovascular events in childhood/adolescence. (alavi2024arterialstrokein pages 4-4, alavi2024arterialstrokein pages 1-2)

9. Inheritance and population

9.1 Inheritance

Predominantly autosomal recessive. (kelana2023caseofseckel pages 1-2, jurca2024clinicalchallengesin pages 4-6)

9.2 Epidemiology (statistics from recent sources; interpret cautiously)

Epidemiologic data are limited and inconsistent across sources: - A 2024 review/case study states Seckel syndrome affects “1 in 10,000 children” and that ~100 cases have been reported. (jurca2024clinicalchallengesin pages 4-6) - A 2022 rehabilitation case report cites Orphanet (2021) and reports an estimated prevalence/incidence of 0.2 per 100,000 live births and also notes the rarity of published families. (souza2022seckelsyndromecase pages 2-4)

Because Seckel syndrome is genetically heterogeneous and historically variably defined within MPD, differences in ascertainment and labeling likely contribute to discrepant estimates. (alkuraya2015primordialdwarfisman pages 1-2, jurca2024clinicalchallengesin pages 1-2)

10. Diagnostics

10.1 Clinical diagnosis

Clinical suspicion is based on the primordial dwarfism pattern (prenatal-onset growth restriction), severe microcephaly, characteristic facial features, and neurodevelopmental delay/intellectual disability. (farcy2023geneticprimarymicrocephalies pages 2-4, kelana2023caseofseckel pages 1-2)

10.2 Genetic testing strategies (real-world workflows)

A 2023 molecularly solved CEP152 case illustrates a practical diagnostic ladder: - Karyotype analysis and CNV-seq were normal. - Trio whole-exome sequencing (WES) identified compound heterozygous CEP152 variants. - qRT-PCR and RT-PCR demonstrated reduced expression and aberrant splicing (exon skipping), with Sanger sequencing confirmation. (zhang2023twonovelvariants pages 1-2)

A 2023 RTTN case similarly used WES to discover a novel biallelic missense variant. (mudassir2023microcephalyshortstature pages 1-2)

10.3 Imaging and complication screening

In the context of neurologic symptoms, a 2024 pediatric case used MRI (DWI/ADC) to confirm acute MCA territory infarction and vascular imaging (MRA/CTA) showing internal carotid narrowing/obliteration and collateralization. (alavi2024arterialstrokein pages 1-2, alavi2024arterialstrokein pages 4-5)

The same report recommends early neuroimaging for children with Seckel syndrome/related MPD when stroke is suspected, and highlights consideration of medical therapy and potential revascularization in moyamoya-like disease (noting evidence remains limited). (alavi2024arterialstrokein pages 4-4)

10.4 Differential diagnosis

Clinical overlap exists with other primordial dwarfism syndromes and short stature disorders; one case-oriented discussion lists alternatives such as Hallermann–Streiff, Dyggve–Melchior–Clausen, and Cockayne syndrome and emphasizes that definitive diagnosis often requires genetic testing. (kelana2023caseofseckel pages 4-5)

11. Outcome / prognosis

Evidence in the retrieved sources is limited and largely case-based. A clinical case report notes that life expectancy can be prolonged and states patients “can live up to 75 years,” but this should be interpreted cautiously given the lack of cohort-level survival analyses in the excerpted evidence. (kelana2023caseofseckel pages 4-5)

A major morbidity driver for a subset of patients is cerebrovascular disease (ischemic stroke, aneurysm, hemorrhage), which—while uncommon—can produce long-term neurological deficits requiring rehabilitation. (alavi2024arterialstrokein pages 3-4, alavi2024arterialstrokein pages 4-4)

12. Treatment

12.1 Disease-modifying therapy

No disease-specific curative pharmacotherapy is established in the retrieved evidence; management is described as supportive. (kelana2023caseofseckel pages 1-2, kelana2023caseofseckel pages 4-5)

12.2 Supportive and rehabilitative care (real-world implementations)

A case-based clinical discussion recommends physiotherapy to maintain mobility and balance, reduce bony deformities, and improve independence, as well as family counseling. (kelana2023caseofseckel pages 4-5)
A PNF/Kabat rehabilitation case (20 sessions over 10 weeks) reported objective improvements in balance/strength/agility measures but not broad ADL scores. (souza2022seckelsyndromecase pages 8-11, souza2022seckelsyndromecase pages 11-12)

12.3 Management of cerebrovascular complications

In a 2024 pediatric stroke case with intracranial vasculopathy, management included aspirin 5 mg/kg; surgical revascularization was not performed due to lack of consent, and the patient received inpatient rehabilitation and ongoing physiotherapy, with residual weakness at 10 months. (alavi2024arterialstrokein pages 3-4, alavi2024arterialstrokein pages 4-5)

MAXO term suggestions (examples): - Supportive care / multidisciplinary management; physical therapy/rehabilitation; antiplatelet therapy (for secondary stroke prevention when indicated).

13. Prevention

Primary prevention of Seckel syndrome is not applicable in the conventional sense because it is congenital genetic disease; prevention focuses on genetic counseling and reproductive planning, which is explicitly referenced in the context of solved molecular diagnoses (e.g., improving pregnancy plans after defining CEP152 variants). (zhang2023twonovelvariants pages 1-2)

14. Other species / natural disease

No naturally occurring veterinary analogs were identified in the retrieved evidence.

15. Model organisms

A landmark mouse model study shows that disruption of Cenpj (a centriole biogenesis regulator) can phenocopy aspects of Seckel syndrome, including growth defects and cellular genomic instability.

Quantitative examples from Cenpj hypomorphic mice include altered glucose response (e.g., 20.5±0.7 mmol/L vs 30.7±1.60 mmol/L at 15 minutes; P = 2.6×10−5) and increased micronucleated erythrocytes (P = 4×10−6), consistent with spontaneous genomic instability. (mcintyre2012disruptionofmouse pages 6-8)

Mechanistically, the authors argue the instability is linked to centriole/centrosome defects rather than defective ATR/ATM DNA damage signaling in that model, supporting mechanistic heterogeneity across Seckel genes. (mcintyre2012disruptionofmouse pages 6-8, mcintyre2012disruptionofmouse pages 1-2)

Recent developments (2023–2024 highlights)

1) 2023—CEP152 variant spectrum expansion in Seckel syndrome 5: A Chinese family was solved by trio-WES and functional RNA assays, identifying CEP152 c.1060C>T (p.Arg354*) and c.1414-14A>G with exon skipping, extending knowledge of non-canonical splice variation. (Published Jan 2023; https://doi.org/10.3389/fgene.2022.1052915) (zhang2023twonovelvariants pages 1-2)

2) 2023—RTTN as a Seckel-spectrum gene in a consanguineous family: A novel biallelic missense RTTN variant c.57G>T (p.Glu19Asp) was reported with microcephaly, short stature, severe intellectual disability, absent speech, and cataracts, broadening the phenotype spectrum. (Published Jun 2023; https://doi.org/10.3390/children10061027) (mudassir2023microcephalyshortstature pages 1-2)

3) 2024—Quantified cerebrovascular risk and stroke phenotype: A 2024 stroke case report summarizes a systematic review reporting CNS vasculopathy 3.16% and moyamoya 1.97% in Seckel syndrome and provides detailed vascular imaging patterns (carotid narrowing/obliteration with collaterals). (Published May 2024; https://doi.org/10.1002/ccr3.8871) (alavi2024arterialstrokein pages 4-4, alavi2024arterialstrokein pages 4-5)

Current applications and real-world implementations

Genomic diagnostics: Trio-WES with reflex transcript assays can solve clinically suspected Seckel syndrome when karyotype/CNV testing is normal, enabling family planning and variant-specific counseling. (zhang2023twonovelvariants pages 1-2)
Natural history and risk surveillance: Observational studies/registries collect longitudinal phenotype, imaging, and genetic data to refine prognosis and management (notably vascular screening).
NCT03139903 (completed; enrollment 30) included cerebral angio-MRI, cognitive testing (WISC-IV), visual acuity, and multidisciplinary evaluations with initiation of supportive care (speech therapy/psychomotricity). (NCT03139903 chunk 1)
NCT04569149 (registry; target ~200; chart review) collects specialist evaluations, surgeries, labs, genetic tests, and imaging (including CT/MRI/MRA) to define natural history and risk factors. (NCT04569149 chunk 1)

Expert opinions / authoritative analysis (as supported by evidence)

A review on primordial dwarfism emphasizes that “Seckel syndrome” has historically been a loosely used label within primordial dwarfism and cautions clinicians to use broader “primordial dwarfism” terminology until specialist subtyping is performed, reflecting genuine phenotypic/genetic overlap within MPD. (alkuraya2015primordialdwarfisman pages 1-2)
A 2024 case report synthesizes available evidence on cerebrovascular anomalies and supports proactive neurovascular evaluation in symptomatic children with Seckel/MPD due to the risk of infarction/hemorrhage. (alavi2024arterialstrokein pages 4-4)

Evidence-backed summary table (knowledge-base ready)

Topic	Key facts (with numbers where available)	Example evidence/quote	Source (first author year, journal)	PMID/DOI/URL if available
Definition / core features	Seckel syndrome is a rare autosomal recessive microcephalic primordial dwarfism characterized by intrauterine and postnatal growth restriction, severe/proportionate microcephaly, intellectual disability, and a characteristic “bird-headed” facies; adult height is reported around 120 cm, childhood short stature about −6 to −8 SD, and newborn OFC about 27 cm with adult HC 39–42 cm in one review (zhang2023twonovelvariants pages 1-2, farcy2023geneticprimarymicrocephalies pages 2-4, jentcy2021seckelsyndrome pages 1-1).	“rare autosomal recessive inherited disorder… mainly characterized by intrauterine and postnatal growth restrictions, microcephaly, intellectual disability, and a typical ‘bird-head’ facial appearance” (zhang2023twonovelvariants pages 1-2)	Zhang 2023, Frontiers in Genetics; Farcy 2023, Cells	DOI: 10.3389/fgene.2022.1052915; https://doi.org/10.3389/fgene.2022.1052915 ; DOI: 10.3390/cells12131807; https://doi.org/10.3390/cells12131807
Identifiers	Curated identifiers directly supported in gathered evidence: OMIM #210600 for Seckel syndrome; ORPHA:808; a trial record also lists “Seckel syndrome 1” C537533 as a MeSH-like term (farcy2023geneticprimarymicrocephalies pages 2-4, jentcy2021seckelsyndrome pages 1-1, NCT03139903 chunk 1).	“OMIM # 210600” and “ORPHA:808” (farcy2023geneticprimarymicrocephalies pages 2-4, jentcy2021seckelsyndrome pages 1-1)	Farcy 2023, Cells; Jentcy 2021, Definitions/Qeios; ClinicalTrials.gov	DOI: 10.3390/cells12131807; https://doi.org/10.3390/cells12131807 ; DOI: 10.32388/9UTNHS; https://doi.org/10.32388/9utnhs ; NCT03139903
Inheritance / nosology	Inheritance is predominantly autosomal recessive; Seckel syndrome is classified within primordial dwarfism, specifically microcephalic primordial dwarfism (MPD) / “Seckel syndrome spectrum disorders” in historical nosology (kelana2023caseofseckel pages 1-2, farcy2023geneticprimarymicrocephalies pages 2-4, jurca2024clinicalchallengesin pages 1-2).	“Seckel syndrome is an extremely rare syndrome with autosomal recessive inheritance” (jurca2024clinicalchallengesin pages 4-6)	Kelana 2023, Open Access Macedonian Journal of Medical Sciences; Farcy 2023, Cells; Jurca 2024, Medicina	DOI: 10.3889/oamjms.2023.10988; https://doi.org/10.3889/oamjms.2023.10988 ; DOI: 10.3390/cells12131807; https://doi.org/10.3390/cells12131807 ; DOI: 10.3390/medicina60111906; https://doi.org/10.3390/medicina60111906
Epidemiology	Evidence is sparse and inconsistent. Reported figures include ~100 cases in the literature/worldwide and estimates of 1 in 10,000 children/births; an Orphanet-derived figure cited in a rehab case report gives 0.2 per 100,000 live births (jurca2024clinicalchallengesin pages 4-6, souza2022seckelsyndromecase pages 2-4, kelana2023caseofseckel pages 1-2).	“Approximately 100 cases have been reported in the literature” and “affecting 1 in 10,000 children” (jurca2024clinicalchallengesin pages 4-6); “estimated prevalence/incidence of 0.2 per 100,000 live births” (souza2022seckelsyndromecase pages 2-4)	Jurca 2024, Medicina; Souza 2022, Research, Society and Development; Kelana 2023, OAMJMS	DOI: 10.3390/medicina60111906; https://doi.org/10.3390/medicina60111906 ; DOI: 10.33448/rsd-v11i2.25080; https://doi.org/10.33448/rsd-v11i2.25080 ; DOI: 10.3889/oamjms.2023.10988; https://doi.org/10.3889/oamjms.2023.10988
Major causal genes	Gathered evidence supports substantial genetic heterogeneity. Recurrently cited genes include ATR, RBBP8, CENPJ, CEP152, CEP63, NIN, DNA2, TRAIP, NSMCE2, CDK5RAP2, and newer spectrum associations including RTTN (zhang2023twonovelvariants pages 1-2, patrick2017atrisa pages 58-61, mudassir2023microcephalyshortstature pages 1-2, mcintyre2012disruptionofmouse pages 1-2).	“Forty cases of Seckel syndrome have been reported to date… due to mutations in the ATR, TRAIP, RBBP8, NSMCE2, NIN, CENPJ, DNA2, CEP152 and CEP63 genes” (mudassir2023microcephalyshortstature pages 1-2)	Mudassir 2023, Children; Zhang 2023, Frontiers in Genetics; Yigit 2015, Molecular Genetics & Genomic Medicine	DOI: 10.3390/children10061027; https://doi.org/10.3390/children10061027 ; DOI: 10.3389/fgene.2022.1052915; https://doi.org/10.3389/fgene.2022.1052915 ; DOI: 10.1002/mgg3.158; https://doi.org/10.1002/mgg3.158
Example pathogenic variants	Specific variants documented in gathered evidence include *CEP152 c.1060C>T (p.Arg354), CEP152 c.1414-14A>G causing exon 12 skipping, and RTTN NM_173630.4:c.57G>T (p.Glu19Asp)**; the CEP152 case had normal karyotype/CNV-seq with pathogenic findings only on trio-WES plus transcript studies (zhang2023twonovelvariants pages 1-2, mudassir2023microcephalyshortstature pages 1-2).	“Two novel variants in CEP152, c.1060C>T (p.Arg354*) and c.1414-14A>G, were identified” (zhang2023twonovelvariants pages 1-2); “Whole-exome sequencing discovered… c.57G > T (p.Glu19Asp)” (mudassir2023microcephalyshortstature pages 1-2)	Zhang 2023, Frontiers in Genetics; Mudassir 2023, Children	DOI: 10.3389/fgene.2022.1052915; https://doi.org/10.3389/fgene.2022.1052915 ; DOI: 10.3390/children10061027; https://doi.org/10.3390/children10061027
Mechanisms / pathways	Two major mechanistic modules emerge: DNA damage response / replication stress (ATR–ATRIP, RBBP8/CtIP, DNA2, TRAIP) and centrosome / centriole biogenesis and mitotic spindle dysfunction (CENPJ, CEP152, CEP63, NIN, CDK5RAP2, RTTN). Downstream consequences include genomic instability, mitotic failure, apoptosis, and impaired growth/neurodevelopment (patrick2017atrisa pages 58-61, mcintyre2012disruptionofmouse pages 6-8, mcintyre2012disruptionofmouse pages 1-2).	“increased cell death due to mitotic failure during embryonic development is likely to contribute to the proportionate dwarfism” (mcintyre2012disruptionofmouse pages 1-2)	McIntyre 2012, PLoS Genetics; O’Driscoll 2012, Cold Spring Harbor Perspectives in Biology; Farcy 2023, Cells	DOI: 10.1371/journal.pgen.1003022; https://doi.org/10.1371/journal.pgen.1003022 ; DOI: 10.1101/cshperspect.a012773; https://doi.org/10.1101/cshperspect.a012773 ; DOI: 10.3390/cells12131807; https://doi.org/10.3390/cells12131807
Diagnostics / testing approach	Diagnosis often begins clinically but increasingly relies on molecular testing. Reported workflows include karyotype, CNV-seq, trio-WES, Sanger confirmation, and RNA studies (qRT-PCR/RT-PCR); in one CEP152 case, karyotype and CNV-seq were normal and trio-WES solved the case (zhang2023twonovelvariants pages 1-2, kelana2023caseofseckel pages 1-2, NCT03139903 chunk 1).	“The karyotype analysis and CNV-seq were normal in the proband… Two novel variants in CEP152… were identified… through trio-WES” (zhang2023twonovelvariants pages 1-2)	Zhang 2023, Frontiers in Genetics; Kelana 2023, OAMJMS; ClinicalTrials.gov NCT03139903	DOI: 10.3389/fgene.2022.1052915; https://doi.org/10.3389/fgene.2022.1052915 ; DOI: 10.3889/oamjms.2023.10988; https://doi.org/10.3889/oamjms.2023.10988 ; NCT03139903
Complications: CNS vasculopathy / stroke	CNS vasculopathy is uncommon but clinically important. A 2024 case report cites a systematic-review estimate of 3.16% (8/253) of Seckel syndrome patients with CNS vasculopathy, with moyamoya disease in 1.97%; mean age was 13.5 years (range 6–19). Reported lesions include carotid narrowing/obliteration, aneurysms, infarction, subarachnoid hemorrhage, and moyamoya/non-moyamoya collateral patterns (alavi2024arterialstrokein pages 4-4, alavi2024arterialstrokein pages 1-2).	“CNS vasculopathy in 3.16% (8/253) of SS patients, with moyamoya disease (MMD) comprising 1.97% of cases” (alavi2024arterialstrokein pages 4-4)	Alavi 2024, Clinical Case Reports	DOI: 10.1002/ccr3.8871; https://doi.org/10.1002/ccr3.8871
Management / treatment	No disease-specific curative therapy is established; management is supportive, including developmental intervention, nutrition/growth monitoring, family counseling, and physiotherapy. A real-world PNF/Kabat rehab case (20 sessions over 10 weeks) improved SPPB 4→8, TUG 28.0→19.9 s, and grip strength by 23.4% (right) and 27.4% (left), though ADLs did not significantly improve. In the 2024 pediatric stroke case, aspirin 5 mg/kg was used when revascularization was not performed (souza2022seckelsyndromecase pages 2-4, souza2022seckelsyndromecase pages 11-12, kelana2023caseofseckel pages 4-5, alavi2024arterialstrokein pages 3-4).	“There is no specific treatment” (kelana2023caseofseckel pages 1-2); “the plan was to continue aspirin to reduce recurrent stroke risk” (alavi2024arterialstrokein pages 4-5)	Souza 2022, Research, Society and Development; Kelana 2023, OAMJMS; Alavi 2024, Clinical Case Reports	DOI: 10.33448/rsd-v11i2.25080; https://doi.org/10.33448/rsd-v11i2.25080 ; DOI: 10.3889/oamjms.2023.10988; https://doi.org/10.3889/oamjms.2023.10988 ; DOI: 10.1002/ccr3.8871; https://doi.org/10.1002/ccr3.8871
Trials / registries	NCT03139903: completed French multicenter observational study, 30 participants, designed to define morphological/epidemiologic parameters and identify new symptoms; included cerebral angio-MRI, specialty assessments, cognitive testing, and supportive-care planning. NCT04569149: recruiting Primordial Dwarfism Registry, target ~200, chart-review based, collecting longitudinal specialist notes, surgery reports, labs, genetic testing, and imaging to define natural history/risk factors and improve care/QoL (NCT03139903 chunk 1, NCT04569149 chunk 1).	“Primary objective/outcome: to visualize any vascular abnormalities via cerebral angiography‑MRI” (NCT03139903 chunk 1); “support preventative treatments and improved quality of life” (NCT04569149 chunk 1)	ClinicalTrials.gov NCT03139903; ClinicalTrials.gov NCT04569149	https://clinicaltrials.gov/study/NCT03139903 ; https://clinicaltrials.gov/study/NCT04569149

Table: This table summarizes high-yield, citation-backed facts on Seckel syndrome for knowledge-base use, including identifiers, genetics, mechanisms, diagnostics, complications, management, and relevant observational studies/registries.

Key evidence gaps (for knowledge-base completeness)

Within the retrieved corpus, ICD-10/ICD-11 codes, MONDO ID, canonical MeSH descriptor ID, robust penetrance/expressivity estimates by gene, and population allele frequencies (gnomAD) were not available; these would require direct querying of OMIM/Orphanet/MeSH/MONDO/ClinVar/gnomAD or dedicated GeneReviews text beyond the excerpts captured here.

References

(farcy2023geneticprimarymicrocephalies pages 2-4): Sarah Farcy, Hassina Hachour, Nadia Bahi-Buisson, and Sandrine Passemard. Genetic primary microcephalies: when centrosome dysfunction dictates brain and body size. Cells, 12:1807, Jul 2023. URL: https://doi.org/10.3390/cells12131807, doi:10.3390/cells12131807. This article has 26 citations.
(zhang2023twonovelvariants pages 1-2): Li Zhang, Yanling Teng, Haoran Hu, Huimin Zhu, Juan Wen, Desheng Liang, Zhuo Li, and Lingqian Wu. Two novel variants in cep152 caused seckel syndrome 5 in a chinese family. Frontiers in Genetics, Jan 2023. URL: https://doi.org/10.3389/fgene.2022.1052915, doi:10.3389/fgene.2022.1052915. This article has 2 citations and is from a peer-reviewed journal.
(mcintyre2012disruptionofmouse pages 1-2): Rebecca E. McIntyre, Pavithra Lakshminarasimhan Chavali, Ozama Ismail, Damian M. Carragher, Gabriela Sanchez-Andrade, Josep V. Forment, Beiyuan Fu, Martin Del Castillo Velasco-Herrera, Andrew Edwards, Louise van der Weyden, Fengtang Yang, Ramiro Ramirez-Solis, Jeanne Estabel, Ferdia A. Gallagher, Darren W. Logan, Mark J. Arends, Stephen H. Tsang, Vinit B. Mahajan, Cheryl L. Scudamore, Jacqueline K. White, Stephen P. Jackson, Fanni Gergely, and David J. Adams. Disruption of mouse cenpj, a regulator of centriole biogenesis, phenocopies seckel syndrome. PLoS Genetics, 8:e1003022, Nov 2012. URL: https://doi.org/10.1371/journal.pgen.1003022, doi:10.1371/journal.pgen.1003022. This article has 109 citations and is from a domain leading peer-reviewed journal.
(kelana2023caseofseckel pages 1-2): Andreas Dhymas Dhyna Martha Kelana, Gusti Ayu Trisna Windiani, Made Arimbawa, Gusti Agung Ngurah Sugitha Adnyana, Made Darma Yuda, Ni Luh Sukma Pratiwi Murti, and Soetjiningsih Soetjiningsih. Case of seckel syndrome in a 9-month-old girl. Open Access Macedonian Journal of Medical Sciences, 11:6-10, Jan 2023. URL: https://doi.org/10.3889/oamjms.2023.10988, doi:10.3889/oamjms.2023.10988. This article has 0 citations.
(mudassir2023microcephalyshortstature pages 1-2): Behjat Ul Mudassir and Zehra Agha. Microcephaly, short stature, intellectual disability, speech absence and cataract are associated with novel bi-allelic missense variant in rttn gene: a seckel syndrome case report. Children, 10:1027, Jun 2023. URL: https://doi.org/10.3390/children10061027, doi:10.3390/children10061027. This article has 10 citations.
(alavi2024arterialstrokein pages 3-4): Samin Alavi, Mitra Khalili, Paniz Mirmoghaddam, Sharareh Kamfar, and Negar Shams. Arterial stroke in a child with seckel syndrome with a pattern of non‐moyamoya vasculopathy. Clinical Case Reports, May 2024. URL: https://doi.org/10.1002/ccr3.8871, doi:10.1002/ccr3.8871. This article has 1 citations.
(jentcy2021seckelsyndrome pages 1-1): M Jentcy and VV Vanniaperumal. Seckel syndrome. Definitions, Feb 2021. URL: https://doi.org/10.32388/9utnhs, doi:10.32388/9utnhs. This article has 0 citations.
(NCT03139903 chunk 1): The Primordial Dwarfisms: Diagnosis, Identification of the Molecular Basis of Seckel Syndrome and Microcephalic Osteodysplastic Primordial Dwarfism Type II. Assistance Publique - Hôpitaux de Paris. 2010. ClinicalTrials.gov Identifier: NCT03139903
(jurca2024clinicalchallengesin pages 1-2): Alexandru Daniel Jurca, Codruța Diana Petchesi, Sânziana Jurca, Emilia Severin, Aurora Alexandra Jurca, and Claudia Maria Jurca. Clinical challenges in diagnosing primordial dwarfism: insights from a mopd ii case study. Medicina, 60:1906, Nov 2024. URL: https://doi.org/10.3390/medicina60111906, doi:10.3390/medicina60111906. This article has 4 citations.
(zhang2023twonovelvariants pages 8-8): Li Zhang, Yanling Teng, Haoran Hu, Huimin Zhu, Juan Wen, Desheng Liang, Zhuo Li, and Lingqian Wu. Two novel variants in cep152 caused seckel syndrome 5 in a chinese family. Frontiers in Genetics, Jan 2023. URL: https://doi.org/10.3389/fgene.2022.1052915, doi:10.3389/fgene.2022.1052915. This article has 2 citations and is from a peer-reviewed journal.
(jurca2024clinicalchallengesin pages 4-6): Alexandru Daniel Jurca, Codruța Diana Petchesi, Sânziana Jurca, Emilia Severin, Aurora Alexandra Jurca, and Claudia Maria Jurca. Clinical challenges in diagnosing primordial dwarfism: insights from a mopd ii case study. Medicina, 60:1906, Nov 2024. URL: https://doi.org/10.3390/medicina60111906, doi:10.3390/medicina60111906. This article has 4 citations.
(alavi2024arterialstrokein pages 2-3): Samin Alavi, Mitra Khalili, Paniz Mirmoghaddam, Sharareh Kamfar, and Negar Shams. Arterial stroke in a child with seckel syndrome with a pattern of non‐moyamoya vasculopathy. Clinical Case Reports, May 2024. URL: https://doi.org/10.1002/ccr3.8871, doi:10.1002/ccr3.8871. This article has 1 citations.
(alavi2024arterialstrokein pages 4-4): Samin Alavi, Mitra Khalili, Paniz Mirmoghaddam, Sharareh Kamfar, and Negar Shams. Arterial stroke in a child with seckel syndrome with a pattern of non‐moyamoya vasculopathy. Clinical Case Reports, May 2024. URL: https://doi.org/10.1002/ccr3.8871, doi:10.1002/ccr3.8871. This article has 1 citations.
(souza2022seckelsyndromecase pages 8-11): Jeferson de Lima Souza, Miburge Bolivar Gois Júnior, Diogo Costa Garção, Elenilton Correia de Souza, Isaac Rafael Silva Lima, and Olga Sueli Marques Moreira. Seckel syndrome: case report of functional motor recovery using proprioceptive neuromuscular facilitation/kabat method. Research, Society and Development, 11:e37111225080, Jan 2022. URL: https://doi.org/10.33448/rsd-v11i2.25080, doi:10.33448/rsd-v11i2.25080. This article has 0 citations.
(souza2022seckelsyndromecase pages 11-12): Jeferson de Lima Souza, Miburge Bolivar Gois Júnior, Diogo Costa Garção, Elenilton Correia de Souza, Isaac Rafael Silva Lima, and Olga Sueli Marques Moreira. Seckel syndrome: case report of functional motor recovery using proprioceptive neuromuscular facilitation/kabat method. Research, Society and Development, 11:e37111225080, Jan 2022. URL: https://doi.org/10.33448/rsd-v11i2.25080, doi:10.33448/rsd-v11i2.25080. This article has 0 citations.
(patrick2017atrisa pages 58-61): Patrick Lang. Atr is a novel therapeutic target for medulloblastoma identified by its role in cerebellar development. Text, 2017. URL: https://doi.org/10.17615/zwrt-bm16, doi:10.17615/zwrt-bm16. This article has 0 citations and is from a peer-reviewed journal.
(mcintyre2012disruptionofmouse pages 6-8): Rebecca E. McIntyre, Pavithra Lakshminarasimhan Chavali, Ozama Ismail, Damian M. Carragher, Gabriela Sanchez-Andrade, Josep V. Forment, Beiyuan Fu, Martin Del Castillo Velasco-Herrera, Andrew Edwards, Louise van der Weyden, Fengtang Yang, Ramiro Ramirez-Solis, Jeanne Estabel, Ferdia A. Gallagher, Darren W. Logan, Mark J. Arends, Stephen H. Tsang, Vinit B. Mahajan, Cheryl L. Scudamore, Jacqueline K. White, Stephen P. Jackson, Fanni Gergely, and David J. Adams. Disruption of mouse cenpj, a regulator of centriole biogenesis, phenocopies seckel syndrome. PLoS Genetics, 8:e1003022, Nov 2012. URL: https://doi.org/10.1371/journal.pgen.1003022, doi:10.1371/journal.pgen.1003022. This article has 109 citations and is from a domain leading peer-reviewed journal.
(farcy2023geneticprimarymicrocephalies media eb9668c0): Sarah Farcy, Hassina Hachour, Nadia Bahi-Buisson, and Sandrine Passemard. Genetic primary microcephalies: when centrosome dysfunction dictates brain and body size. Cells, 12:1807, Jul 2023. URL: https://doi.org/10.3390/cells12131807, doi:10.3390/cells12131807. This article has 26 citations.
(farcy2023geneticprimarymicrocephalies media 1a99a141): Sarah Farcy, Hassina Hachour, Nadia Bahi-Buisson, and Sandrine Passemard. Genetic primary microcephalies: when centrosome dysfunction dictates brain and body size. Cells, 12:1807, Jul 2023. URL: https://doi.org/10.3390/cells12131807, doi:10.3390/cells12131807. This article has 26 citations.
(farcy2023geneticprimarymicrocephalies media 0b042e40): Sarah Farcy, Hassina Hachour, Nadia Bahi-Buisson, and Sandrine Passemard. Genetic primary microcephalies: when centrosome dysfunction dictates brain and body size. Cells, 12:1807, Jul 2023. URL: https://doi.org/10.3390/cells12131807, doi:10.3390/cells12131807. This article has 26 citations.
(farcy2023geneticprimarymicrocephalies media c608a08c): Sarah Farcy, Hassina Hachour, Nadia Bahi-Buisson, and Sandrine Passemard. Genetic primary microcephalies: when centrosome dysfunction dictates brain and body size. Cells, 12:1807, Jul 2023. URL: https://doi.org/10.3390/cells12131807, doi:10.3390/cells12131807. This article has 26 citations.
(alavi2024arterialstrokein pages 1-2): Samin Alavi, Mitra Khalili, Paniz Mirmoghaddam, Sharareh Kamfar, and Negar Shams. Arterial stroke in a child with seckel syndrome with a pattern of non‐moyamoya vasculopathy. Clinical Case Reports, May 2024. URL: https://doi.org/10.1002/ccr3.8871, doi:10.1002/ccr3.8871. This article has 1 citations.
(souza2022seckelsyndromecase pages 2-4): Jeferson de Lima Souza, Miburge Bolivar Gois Júnior, Diogo Costa Garção, Elenilton Correia de Souza, Isaac Rafael Silva Lima, and Olga Sueli Marques Moreira. Seckel syndrome: case report of functional motor recovery using proprioceptive neuromuscular facilitation/kabat method. Research, Society and Development, 11:e37111225080, Jan 2022. URL: https://doi.org/10.33448/rsd-v11i2.25080, doi:10.33448/rsd-v11i2.25080. This article has 0 citations.
(alkuraya2015primordialdwarfisman pages 1-2): Fowzan S. Alkuraya. Primordial dwarfism: an update. Current Opinion in Endocrinology & Diabetes and Obesity, 22:55–64, Feb 2015. URL: https://doi.org/10.1097/med.0000000000000121, doi:10.1097/med.0000000000000121. This article has 25 citations.
(alavi2024arterialstrokein pages 4-5): Samin Alavi, Mitra Khalili, Paniz Mirmoghaddam, Sharareh Kamfar, and Negar Shams. Arterial stroke in a child with seckel syndrome with a pattern of non‐moyamoya vasculopathy. Clinical Case Reports, May 2024. URL: https://doi.org/10.1002/ccr3.8871, doi:10.1002/ccr3.8871. This article has 1 citations.
(kelana2023caseofseckel pages 4-5): Andreas Dhymas Dhyna Martha Kelana, Gusti Ayu Trisna Windiani, Made Arimbawa, Gusti Agung Ngurah Sugitha Adnyana, Made Darma Yuda, Ni Luh Sukma Pratiwi Murti, and Soetjiningsih Soetjiningsih. Case of seckel syndrome in a 9-month-old girl. Open Access Macedonian Journal of Medical Sciences, 11:6-10, Jan 2023. URL: https://doi.org/10.3889/oamjms.2023.10988, doi:10.3889/oamjms.2023.10988. This article has 0 citations.
(NCT04569149 chunk 1): Angela Duker. Primordial Dwarfism Registry. Nemours Children's Clinic. 2008. ClinicalTrials.gov Identifier: NCT04569149

Ask OpenScientist

OpenScientist Report

Classifications

Inheritance

Subtypes

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Source YAML

References & Deep Research

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

Seckel syndrome (microcephalic primordial dwarfism): disease characteristics report

Target disease

1. Disease information

1.1 Definition and overview (current understanding)

1.2 Key identifiers (as available in retrieved evidence)

1.3 Common synonyms / alternative names

2. Etiology

2.1 Primary causal factors

2.2 Risk factors

2.3 Protective factors / gene–environment interactions

3. Phenotypes

3.1 Core phenotypes (with ontology suggestions)

3.2 Notable complications with quantitative data: CNS vasculopathy / stroke

3.3 Quality of life / function (reported intervention outcomes)

4. Genetic / molecular information

4.1 Causal genes (examples supported in retrieved evidence)

4.2 Pathogenic variants (explicit examples from 2023–2024 literature in this corpus)

4.3 Functional consequences (high-level)

5. Environmental information

6. Mechanism / pathophysiology

6.1 Mechanistic model (causal chain)

6.2 Pathways, processes, cell types (ontology suggestions)

6.3 Visual evidence (genes/pathways summary)

7. Anatomical structures affected

7.1 Organ/system level (high-level)

7.2 Tissue/cell level

7.3 Subcellular level (GO Cellular Component suggestions)

8. Temporal development

9. Inheritance and population

9.1 Inheritance

9.2 Epidemiology (statistics from recent sources; interpret cautiously)

10. Diagnostics

10.1 Clinical diagnosis

10.2 Genetic testing strategies (real-world workflows)

10.3 Imaging and complication screening

10.4 Differential diagnosis

11. Outcome / prognosis

12. Treatment

12.1 Disease-modifying therapy

12.2 Supportive and rehabilitative care (real-world implementations)

12.3 Management of cerebrovascular complications

13. Prevention

14. Other species / natural disease

15. Model organisms

Recent developments (2023–2024 highlights)

Current applications and real-world implementations